Etoile du Sahel of Tunisia stunned Egyptian double winners Zamalek on Sunday to virtually clinch a place in the Confederation Cup final.
Zamalek's Egyptian rivals Al Ahly also lost their semi-final first leg going down 1-0 to Orlando Pirates of South Africa in Soweto.
Ahly have home advantage for the second leg next Sunday in Suez while Zamalek host Etoile a day earlier in Cairo.
The two-legged final is set for the 20-22 November and a week later.
Marouane Tej scored twice and Baghdad Bounedjah, Alaya Brigui and substitute Saddam Ben Aziza once for the 2015 Tunisian league runners-up.
Ayman Hefny had halved a two-goal deficit with a goal midway through the first period, but it was a rare moment of joy for the Egyptian league and cup holders.
Etoile had scored just four goals in three group games en route to the last four of the tournament, while Zamalek had conceded just three goals in three away group games.
An early goal gave South Africa's Orlando Pirates a 1-0 victory over Al Ahly of Egypt on Saturday in their semi-final first leg.
Thamsanqa Gabuza was the ninth minute match winner against the title holders on a warm evening at Orlando Stadium in Soweto.
The tall striker connected with a low cross and, from an acute angle, steered the ball with his right foot just beyond the reach of goalkeeper Sherif Ekramy.
"Our first priority was to win without conceding a goal at home and we achieved that," said Pirates coach and former South Africa midfielder Eric Tinkler.
"We wanted to catch Ahly through counter-attacks, but our plan largely failed because we played the ball to the feet of our attackers instead of over the Egyptian defence.
"It is half-time in the tie and we are one goal ahead. Now we have to protect that lead and try and score some away goals."