In the following April Margaret and Don Juan were wedded in the cathedral of Burgos.

The union was followed by a series of catastrophes in the Spanish royal family.

While on his way with his wife to attend the marriage of his older sister Isabel with the King of Portugal, Juan caught a malignant fever and expired at Salamanca in October, 1497.
The newly-married Queen of Portugal now became the heiress to the crowns of Aragon and Castile, but she died a year later and shortly afterwards her infant son.

The succession therefore passed to the younger sister, Juana; and Philip the Fair, the heir of the House of Austria and already through his mother the ruler of the rich Burgundian domain, became through his wife the prospective sovereign of the Spanish kingdoms of Ferdinand and Isabel.

Fortune seemed to have reserved all her smiles for the young prince, when on February 24, 1500, a son was born to him at Ghent, who received the name Charles.