The Algerian side won the 2014 tournament in November, beating AS Vita Club on the away goals rule after the teams finished 3-3 on aggregate over two legs.
ES Setif are one of seven sides who have been handed byes from the preliminary stages.
Egyptian outfit Al Ahly - who have won a record eight Champions League crowns - Tunisian duo CS Sfaxien and Esperance, Cameroonian team Coton Sport, AC Leopards of Congo and TP Mazembe of the Democratic Republic of Congo are also exempt from the preliminary round.
Ghanaian champions Asante Kotoko - who are two-time winners of the tournament - open their account against East End Lions of Sierra Leone.
Two other former holders, Enyimba of Nigeria and Raja Casablanca of Morocco, take on Buffles du Borgou of Benin and Diables Noirs of Congo respectively.
Gor Mahia, the reigning Kenyan champions, start against Madagascar.
The preliminary round of the tournament begins between February 13 and 15, with the return legs of those ties set to be played a fortnight later.