Some cardinals opposed this, but Adrian pushed his decision through and William was created Cardinal-priest of St. John and Paul on 10 September 1523.

[2] After the death of Adrian in 1523, William of Enckevoirt maintained his high positions and continued his involvement in politics, such as the transfer of all lands of the Bishopric of Utrecht to Charles V, Holy Roman Emperor, and the crowning of Charles V as emperor in 1530.

During the 1527 sacking of Rome by imperial troops, he paid 40,000 scudi to Captain Odone to protect his house and properties.

William, who was the executor of Adrian VI's will, took the initiative in erecting a funerary monument for him in Santa Maria dell'Anima.

His monument, created by Giovanni Mangone, was originally located opposite of Adrian VI's tomb, but it was moved in 1575.