The Egyptian outfit overcame Orlando Pirates 3-1 on aggregate in last year's final to claim the title for the eighth time in their history.
However, Mohamed Youssef's men head into the second leg of their tie with Tanzanian side Young Africans 1-0 down following a disappointing first leg.
But Faouzi Benzarti's men will have to come from behind if they are to have any chance of returning to that competition following a 1-0 loss to Horoya of Guinea.
By contrast, five-time champions Zamalek have a 1-0 advantage in their tie with Kabuscorp of Angola, while last-season's semi-finalists, ES Tunis, have the benefit of away goals after a 3-2 win at Kenya's Gor Mahia.
Ivorian side Sewe Sport's prospects of qualifying for the next round hang in the balance on the back of an enthralling 3-3 draw in the first leg clash with Barrack Young Controllers of Liberia.
The winner of that tie faces a meeting with either two-time winners TP Mazembe or Les Astres of Cameroon, who are locked at 1-1 after the first leg.
Cotonsport reached the last four in 2013 but head into the second leg trailing Flambeau de l'Est 1-0, however, 2006 finalists CS Sfaxien host Dedebit leading 2-1 from the first game.
It is all to play for in the ties between Dynamos and AS Vita club and Stade Malien and Al Hilal Omdurman, which are both goalless ahead of the decisive leg.
