For nearly five hundred years, the Venetian and the Byzantine empires enjoyed an immensely profitable centuries-long commercial and military alliance that dominated shipping and trade in the Mediterranean and its gateways to Europe and the East. While Constantinople was much larger and more powerful than the Italian city-state, the skillful, well-organized Venetian traders were able to out-negotiate the Byzantine trade ministers and benefited from disproportionately favorable terms of treaties and contracts. The Byzantine Emperor, responding to mounting domestic pressure, retaliated by imprisoning thousands of Venetian sailors, seizing ships and cargo. With increasing provocation, Venice had no choice but to go to war with Constantinople in 1171 and ended up suffering a crushing defeat.

The Byzantine victory would be short-lived, though, as would the empire's dominance on both sides of the Mediterranean. In 1204, the doge, or ruler, of Venice, along with other European powers, organized the Fourth Crusade with the goal of conquering the Byzantine capital of Constantinople and replacing its Eastern Orthodox state religion with Roman Catholicism. Weakened as it was by internal problems like poor administration of its territories, political feuding, incompetence, and corruption, Constantinople fell to the vengeful crusaders who established a Latin dynasty that was itself short-lived.

In 1261, Michael VIII Palaiologos recaptured the Byzantine throne and established a Greek dynasty that would endure for two hundred years. Trade was reestablished with Venice, but Byzantine influence was diminishing in the Balkans and Middle East, as was Christianity's. In Turkey, the Muslim Ottomans were emerging as the regional superpower and would themselves sack Constantinople in 1453 and establish their capital, from which they would exert control over the former Roman and Byzantine empires for more than four centuries.

There were many factors that weakened and ultimately contributed to the fall of the Byzantine Empire. It would certainly be unfair to blame it all on the Venetians. However, there were a few factors in trade relations between them that led to a weakening of Byzantium.

The main factor stemmed from an old military alliance between Byzantium and Venice. Between 1081 and 1084, the powerful Venetian navy successfully helped Byzantium repel a series of attacks by the Normans. In gratitude, the Byzantines granted Ventitian merchants tariff-free trade in much of their empire. This was ultimately shortsighted, as it allowed the Venetians to dominate trade in the region while cutting Constantinople out of much of the lucrative business.

By the twelfth century, relations were starting to sour between the two nations. The Byzantine emperors were beginning to understand that their commercial relationship with the Venetians was rather one-sided. When Emperor John II refused to renew the treaty with Venice, the Venetians sent a massive naval exhibition against several Byzantine territories in 1124.

Unable to stop them, John II was compelled to sign another treaty with Venice and gave them even more access to Mediterranean markets than before. With the balance of commercial power decidedly in favor of the Venetians, Byzantium was never fully able to make itself the economic powerhouse that it could have been even within its own territories.

Venetian economic motives and activities undoubtedly contributed to the fall of the Byzantine Empire.

Byzantine emperor Alexius Comnenus, though considered a very able and successful ruler by most historians, made what amounted to a deadly mistake in 1082. In an effort to secure military (and particularly naval) support against the Normans, he granted the Venetians unrestricted trading rights in his empire. The generous chrysobull (golden bull) of privileges paved the way for Byzantium's loss of control over its own economy; it also allowed Venice, a future enemy, to amass wealth and gain strength at the expense of Byzantium.

The Venetians, together with the Franks, subsequently sacked Constantinople during the Fourth Crusade (1201–04). The motives were complex but primarily economic. It was the Venetian desire to get paid for their provision of a navy to the Franks that led the crusade afield from its initial destination of Jerusalem to Zara and then Constantinople. Furthermore, the Venetians had long coveted the riches of Byzantium. An examination of primary sources makes clear the role of greed.

After the sack, aside from dividing up the spoils, the Venetians, together with the Franks and the papacy, set up what is called the Latin Empire (1204–61). What was previously a highly centralized state became a patchwork of feudal-like entities and, although the Byzantine Empire was liberated after fifty-five years by the Empire of Nicaea, it never fully recovered to its former strength. By the mid-1300s, the Byzantine emperors became vassals of the Turks, and then, in 1453, Constantinople fell to the Ottomans.

The Byzantine Empire crumbled for a number of reasons; chief among these reasons were the numerous civil wars the empire experienced. However, there were other contributing factors to the empire's demise as well, including trade with the Venetians.

Venice and Genoa were economically prosperous throughout the 1200s and 1300s. Venice, being a collection of islands, controlled a very strategic trade route, which gave it hefty power over commerce in the Mediterranean. The Byzantine Empire was forced into trade agreements that saw large customs and trade fees levied against it. At one point, it was estimated that over 80% of the empire's entire trade revenue was being paid in fees to the governments of Venice and Genoa. This toll strained the Byzantine economy, eventually contributing to its collapse.

Byzantine and Venetian relations had long been troubled. Venetian trade dominated much of the Mediterranean. They had been given special trading rights within the empire as far back as Justinian in the fifth century. In return, Venice's powerful fleet protected Byzantine ships.

Venice did come to the aid of the Byzantine Empire when it was attacked by Normans. In return, Venice received a virtual trade monopoly. Then Venetians were falsely accused of an attack on Byzantine territory. Their rivals the Genoans also attacked Venetians in Byzantium. There was a failed treaty between Venice and the Byzantine Empire and, later, two wars between them, plus a war between Venice and Genoa.

The Byzantine Empire began to fall because of the Fourth Crusade sacking its capital. Venetians had been most of the soldiers the empire sent on the Crusades. When other Crusaders turned on Byzantine, it became weakened and was gradually conquered by the Ottoman Turks.