- May 6 - Spanish and German troops led by the Duke of Bourbon sack Rome, forcing Pope Clement VII to make peace with Charles V.
- May 16 - Florentines drive out the Medici for a second time and Florence re-establishes a republic.
- Spanish conquest of Guatemala highlands completed; first Guatemala City founded (Ciudad Vieja)
- Spanish Conquistador Francisco de Montejo invades Yucatan
- Battle of Tokay - Ferdinand of Austria defeats John Zapolya and takes over most of Hungary. John appeals to the Turks for help.