Renzo’s final trip to Milan is defined by the terrible plague sweeping through the city. As the people of Milan begin to collapse and die in the streets, they must reckon with the plague as an act of God. The people’s explanation for the causes and the spread of the plague symbolize their connection with the divine. At no point is anyone willing (at least in the narrator’s telling of events) to categorize the plague as a punishment from God. Rather, they blame the plague on human conspiracies and dark magic. The anointers spreading the plague with their unguents become more of a focus than some moral failing of the city at large, which might stir a wrathful God. The Milanese willingness to invent conspiracies during a time of suffering speaks to their relationship with God. They do not believe that they have committed any moral infringement, so they prefer to blame one another rather than their God.

When the plague hits Milan, the city is already on the precipice of collapse. Due to years of famine and war, the distant Spanish rulers and the governors they appoint are more interested in broad, international matters than whatever is happening on the streets of Milan.