On 18 May 1514, Francis married his second cousin Claude, the daughter of King Louis XII of France and Duchess Anne of Brittany. The couple had seven children:
Louise (19 August 1515 –-21 September 1517) - died young, engaged to Charles I of Spain almost from birth until death.
Charlotte (23 October 1516 –-8 September 1524) - died young, engaged to Charles I of Spain from 1518 until death.
Francis (28 February 1518 –-10 August 1536), who succeeded Claude as Duke of Brittany, but died unmarried and childless.
Henry (31 March 1519 –-10 July 1559), who succeeded Francis I as King of France and married Catherine de' Medici, by whom he had issue.
Madeleine (10 August 1520 –-2 July 1537), who married James V of Scotland and had no issue.
Charles (22 January 1522 – 9 September 1545), who died unmarried and childless.
Margaret of France, Duchess of Berry (5 June 1523 – 14 September 1574), who married Emmanuel Philibert, Duke of Savoy, in 1559 and had issue.