He inherited his father's possessions in Palencia and the castle of Medina de Rioseco.
Fadrique Enríquez was hot-tempered and was banished to Sicily after a row with Queen Isabella I of Castile.
Fadrique Enríquez himself was count of Melgar, lord of Medina de Rioseco, Mansilla, Rueda, Aguilar, and Villabrajima and was one of the richest persons in Spain.
On his return, he escorted Philip's sister, Margaret, to Spain to be married to prince John.
In 1520 he became, together with his cousin Íñigo Fernández de Velasco, 2nd Duke of Frías, governor of Spain in the absence of Charles V. He brought peace and was rewarded by the Emperor with the Order of the Golden Fleece.