Although both Machiavelli and Guicciardini shared many views on the practical application of political power, their approaches did have notable differences.
Overall, Guicciardini took a much less cynical approach to human behavior. Guicciardini felt that although a ruler could control his state with the same conniving manipulations that Machiavelli describes, it is also possible to rule by winning the genuine trust of allies and subjects. Machiavelli seems to have believed that people only act out of self-interest. He wrote that it should be assumed that anyone who has risen to a position of power could only accomplish this through wicked deeds. Guicciardini disagreed. Responding to Machiavelli, he countered that there is inherent goodness within all people. However, Guicciardini conceded that many powerful people are still corrupted by their positions and can stray from the good path.
The two also disagreed on the notion of using collective punishment to make an example. Machiavelli argued that a ruler should often resort to inflicting public and widespread punishment and violence on people, even good people, in order to showcase their power. He wrote that this is especially the case when a ruler has recently acquired a city or territory. To make his power known "a new prince in a city or province taken by him must make everything new" (Discourses XXVI). Guicciardini considered this too violent a response. He argued that such action ultimately showed a ruler's weakness and that the demonstration of fairness, justice, and restraint made a ruler more secure in the end.
There are many other examples of where Guicciardini and Machiavelli diverge. Many can be found in Guicciardini's Considerazioni intorno ai "Discorsi" del Machiavelli sopra la prima deca di Tito Livio, where he responds directly to Machiavelli's observations of Ancient Rome. To sum up their contrasts, Guicciardini believed in the inherent goodness of people and Machiavelli rejected it. Guicciardini also thought that Machiavelli took too inflexible of a stance of how to effectively rule and that there is ultimately room for nuance in maintaining power.