Victor Frankenstein's guilt (as seen in Mary Shelley's novel Frankenstein) does not arise until his creature begins to act out against society (because of Victor's alienation). Up until the death of William, the creature's first victim), Victor feels no guilt for creating the creature.
When Victor's creature first opens its eyes, Victor feels no guilt. Instead, Victor is horrified at and disappointed by his creature.
Mingled with this horror, I felt the bitterness of disappointment; dreams that had been my food and pleasant rest for so long a space were now become a hell to me; and the change was so rapid, the overthrow so complete!
Victor's guilt for creating the creature first becomes a thought after he hears of William's death and he sees the creature in a flash of lightening.
Could he be (I shuddered at the conception) the murderer of my brother?...Nothing in human shape could have destroyed the fair child. He was the murderer! I could not doubt it.
Here, Victor comes to realize the monstrosity of his creature. He now understands what he has unleashed upon the earth. From this point forward, Victor continues to worry about what the creature will do. His guilt becomes even more evident when he worries about what the creature will do to his family after he destroys the mate he agreed to make for the creature.
Therefore, the direct causes for Victor's guilt are the deaths of William, Justine, his father, Henry, and Elizabeth.
In Victor's creation and rejection of The Creature, The Creature turned to murdering all of Frankenstein's loved ones. The Creature strangled William (Victor's younger brother), Henry (Victor's best friend), Elizabeth (Victor's cousin/sister/lover), and set up Justine for the murder of William. Victor feels responsible for these horrific acts of The Creature. Therefore, Victor has an enormous amount of guilt.
He created a monster! He killed his brother and put a woman in jail because he didn't want to confess that he created a monster. He didn't want people to think he was crazy!