Etoile have won the African version of the UEFA Europa League twice, Raja are the trophy-holders and Zamalek can boast of nine CAF titles.
But the north African trio have not made the expected impact since the four groups kicked off with Raja drawing twice and Etoile and Zamalek collecting just one point each.
Raja play fellow Moroccans Renaissance Berkane in Group A on matchday 3, Etoile face in-form Enugu Rangers of Nigeria in Group B and Zamalek meet Petro Atletico of Angola in Group D.
Zesco United of Zambia are the exception among the four top seeds having won their Group C opener, but they then lost their first away match.
AFP Sport previews the third series of matches as the 16 contenders for eight quarter-finals places begin a hectic schedule of playing on four consecutive Sundays.
Group A
Recently hired Raja coach Patrice Carteron from France is under pressure as his side have won just one their last five qualifying and group matches, and that was by a solitary goal.
The impressive home and away from that took Raja to success in the competition last year has deserted them and their leading scorer in Africa, two-goal Badr Banoun, is a centre-back.
Hassania Agadir, the third Moroccan club in the section, host AS Otoho Oyo of Congo Brazzaville needing maximum points to get back into contention for a top-two finish.
Group B
Enugu are the only unbeaten side left in the Confederation Cup with six victories and two draws as they prepare to tackle Etoile in their Mediterranean fortress of Sousse.
Etoile are virtually unbeatable when the 30,000-seat Stade Olympique is packed so the matchday 1 loss to fellow Tunisians CS Sfaxien came as a shock.
Enugu, hoping to become the first Nigerian winners of the 16-year-old competition, forced a matchday 2 draw at Sfaxien and will aim to take at least a point away from Sousse.
Group C
Zambian contenders Nkana and Zesco will want to continue a trend of home victories in this section when they host Asante Kotoko of Ghana and Al Hilal of Sudan respectively.
Captained by striker Walter Bwalya, Nkana aim to extend a 58-match record of never losing at home in a CAF competition since their 1983 debut.
Hilal have appointed Tunisian Nabil al Kouki coach for a third time having sacked his compatriot, Irad Zafouri, after a matchday 2 loss at Nkana this month.
Group D
Bottom-of-the-table Zamalek last won a CAF title 16 years ago and must secure maximum points against Petro in Alexandria to retain a realistic chance of reaching the knockout stage.
The White Knights boast an impressive squad with several Egyptian stars, Tunisians Hamdi el Nagguez and Ferjani Sassi and Moroccans Khalid Boutaib and Hamid Ahaddad.
But an untypically porous defence conceded four goals away to Gor Mahia of Kenya, and a last-minute equaliser to surprise group leaders NA Hussein Dey of Algeria.
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