The Italian War of 1542–1546 was a conflict late in the Italian Wars, pitting Francis I of France and Suleiman I of the Ottoman Empire against the Holy Roman Emperor Charles V and Henry VIII of England. The course of the war saw extensive fighting in Italy, France, and the Low Countries, as well as attempted invasions of Spain and England. The conflict was inconclusive and ruinously expensive for the major participants.
The war arose from the failure of the Truce of Nice, which ended the Italian War of 1536–1538, to resolve the long-standing conflict between Charles and Francis—particularly their conflicting claims to the Duchy of Milan. Having found a suitable pretext, Francis once again declared war against his perpetual enemy in 1542.