Following the death of his wife, Isabella I, Ferdinand had to yield the government of Castile to his son-in-law Philip of Habsburg (1478–1506), who assumed power in the name of his wife Joanna (1479–1555), Isabella's heiress.
A new male heir would displace Joanna (and by extension her husband) from the line of succession. He negotiated with King Louis XII of France for a marriage, hoping to gain accession to the throne of Navarre. At the Treaty of Blois, Louis agreed to have his niece Germaine of Foix marry Ferdinand. (Germaine was also Ferdinand's niece her paternal grandmother, Eleanor of Navarre, being Ferdinand's much older half-sister.) Louis XII also ceded in the treaty his weak claim to the Kingdom of Naples (already controlled by Aragon) and Kingdom of Jerusalem (controlled by neither) to his niece, conditional on a male child being produced. The marriage, between Ferdinand and Germaine, took place in March 1506.
In 1506 Philip of Habsburg died and Ferdinand became regent of Castile for his mentally unstable daughter Joanna. Ferdinand and Germaine did have a son, John, Prince of Girona on 3 May 1509, but he died shortly after birth. Despite the use of love potions, they did not have another.
Ferdinand died of health problems in 1516, leaving Germaine a widow. Ferdinand's successors were Joanna and her son Charles. Ferdinand did, however, leave Germaine a yearly income of 50,000 gold florins, and exhorted his grandson Charles in his last letter not to abandon her.
In 1517, Charles moved from the Netherlands to Castile as the new King of Castile and Aragon. Germaine moved from Aragon to Castile to join his court as well, where the 17-year-old king took well to his 29-year-old stepgrandmother. He organized several tournaments and banquets in her honor. A year or thereabouts later, Germaine gave birth to a daughter, Isabel. It is widely speculated among historians that Charles was Isabel's father; Germaine refers to her in her will as the "Infanta Isabel"—a title that only makes sense if her father was the King.