His early and unexpected death of smallpox at the age of 19 in Rome during a pilgrimage and Grand Tour left a deep mark in history.

Karl Frederick's Dutch tutor Stephanus Winandus Pighius created a literary monument for his pupil in his Hercules Prodicius, published at the Plantin Press in Antwerp in 1587.

Pope Gregory XIII was very attached to his guest, as he hoped that the young Prince would later have a favourable effect on the neighbouring Protestant countries.

Karl Frederick was buried across from Pope Adrian VI, in the Santa Maria dell’Anima, the church in Rome of the Holy Roman Empire of the German nation.

His magnificent grave monument was designed by his tutor Pighius, and executed by the sculptors Nicolas Mostaert and Gillis van den Vliete.