Frederick received papal permission to redirect ecclesiastical revenues to support this preparatory academy for up to 60 poor students under the oversight of the arts faculty of the University of Heidelberg.
Under the leadership of Zacharias Ursinus, the Collegium became a leading center of Reformed theological education in the Holy Roman Empire and enrollments increased.
Under Elector Ludwig IV, the institution returned to Lutheranism in 1577, and Reformed students left the school en masse.
The institution took on a Reformed character again during and after the regency of Count Palatine Johann Casimir from 1584, and there was a concomitant exodus of Lutheran students.
After the restoration of the Palatine Wittelbachs in the aftermath of the war, Elector Karl Ludwig empowered the leading Swiss Scholar Johann Heinrich Hottinger to reopen the Collegium in 1656.