The region was an enclave within the Kingdom of France, comprising the area around the city of Avignon (itself always a separate comtat) roughly between the Rhône, the Durance and Mont Ventoux, and a small exclave located to the north around the town of Valréas purchased by Pope John XXII.

These lands in the Holy Roman Empire belonged to Joan, Countess of Toulouse, and her husband, Alphonse, Count of Poitiers.

Avignon was sold to the papacy by Joanna I, Queen of Naples and Countess of Provence, in 1348,[2] whereupon the two comtats were joined to form a unified papal enclave geographically, though retaining their separate political identities.

The enclave's inhabitants did not pay taxes and were not subject to military service, making life in the Comtat considerably more attractive than under the French Crown.

The Carpentras synagogue, built in the 14th century, is the oldest in France, and until the French Revolution preserved a distinctive Provençal Jewish tradition.

Papal control continued until 1791, when an unauthorized plebiscite, under pressure from French revolutionaries, was held and the inhabitants voted for annexation by France.

A few years later, Vaucluse département was created based on Comtat Venaissin including the exclave of Valréas and a part of the Luberon for the southern half.

Most of the incumbents were in fact prelates, either Archbishops or Bishops, and the Rector therefore had the right to wear a purple garb, similar to that of an Apostolic Chamberlain.