June 29 – Montecuhzoma was killed in some battle following Hernán Cortés' return in Tenochtitlan, Mexico.
Unknown date – Sent to discover the marvels of the New World, the Santiago disappeared on the route taken during Ponce de León's search for the Fountain of Youth. Ponce de León died at some point on the wreck of his ship. Note: In real-world history, Ponce de León died on Cuba in 1521 because of a wound from a poisoned arrow. But according to promotional material for Pirates of the Caribbean: On Stranger Tides, Ponce de León died aboard the Santiago at some point during his search for the Fountain.