Visiting Atalanta shocked top favourites Liverpool 3-0 at Anfield in the Europa League quarter-finals on Thursday in another major setback for Jürgen Klopp's men, while unbeaten Bayer Leverkusen marched on with a 2-0 win over West Ham United.
Gianluca Scamacca scored a 38th and 61st-minute brace, and Mario Pasalic wrapped up matter in the 83rd to put the Italians into pole position for a semi-final berth in their home leg next week.
Defeat for Liverpool came after they were held 2-2 by Manchester United on Sunday and lost the Premier League lead to Arsenal in a three-way title fight also involving title holders Manchester United.
"Obviously it's not great. A very, very disappointing evening. Too many individual mistakes and we got punished for it. It feels bad," Liverpool captain Virgil van Dijk told TNT Sports.
"A very disappointing night for all of us but we can't dwell on it for too long. We need everyone to look forward to another big game. We have to switch back onto getting results.
Bundesliga champions-elect Bayer Leverkusen defeated Conference League winners West Ham from late goals by Jonas Hofmann and Victor Boniface who had both come on in the 76th.
Xabi Alonso's Leverkusen stretched their unbeaten run all season to 42 matches, of which they have won 37, and keep their treble chances alive. They can clinch a first Bundesliga title on Sunday and are also in the German Cup final.
"We knew we had to be patient against a deep defending opponent. We showed belief, quality and patience. The second goal was brutally important for next week," midfielder Granit Xhaka told broadcasters RTL.
In the other games, last year's finalists Roma drew first blood in an Italian duel with a 1-0 victory at AC Milan, and Benfica defeated Olympique Marseille 2-1.
Liverpool had a shaky start against Atalanta, and a took a huge early save from goalkeeper Caoimhin Kelleher to keep out Mario Pasalic at close range.
At the other end, Darwin Nunez fired wide when he should have done better, and Harvey Elliott's curling shot went against the crossbar.
Atalanta were undeterred and drew first blood in the 38th when Davide Zappacosta had too much space on the right wing, and Gianluca Scamacca converted his low cross into the near corner, with Kelleher not looking good.
Liverpool's Dominik Szoboszlai, Mohamed Salah and Andy Robertson came on for the second half but it only got worse for the Reds when Scamacca struck again completely unmarked off Charles de Ketelaere just after the hour.
Teun Koopmeiners came close to a third which finally happened with seven minutes left from Pasalic in what could have been Klopp's last European match at Anfield ahead of his summer departure.
Atalanta had also won at Anfield, then empty owing to the coronavirus pandemic, in the 2020-21 group stage, a 2-0 scoreline after Liverpool had triumphed 5-0 in Bergamo, a big win they now need again.
Leverkusen started strongly against the Hammers whose goalkeeper Lukasz Fabianski denied a backheeler from Patrik Schick and then Alejandro Grimaldo.
West Ham's Lucas Paqueta was lucky to escape with a booking after a challenge against Amine Adli, which however sees him suspended for the return leg, and he flirted with an early dismissal again two minutes later when he was too late against Florian Wirtz.
Fabianski was again on his guard against Schick's header, and against a dangerous Adli effort with a little help of the crossbar before Leverkusen finally broke through thanks to their substitutes.
Hofmann volleyed home in the 83rd in a post-corner scramble, and then crossed for Boniface to head the second at the far post in the first seconds of stoppage time.
Fabianski said the second goal hurt because it gives Leverkusen "a bit more confidence." But, having beaten Freiburg 5-0 at home after a 1-0 first leg defeat in Germany in the previous round, he vowed: "We won't give up. We have to believe and respond in the second leg."
Milan dominated the early stages against Roma but it was the visitors who took a 17th minute lead from Gianluca Mancini's header into the far corner, and they defended the slender lead until the end.
In Lisbon, Rafa Silva gave Benfica a 16th-minute lead, and veteran Angel di Maria made it 2-0 shortly after the restart in a one-two with David Neres. But Pierre-Emerick Aubameyang in the 67th kept Marseille in the tie.
At half-time, Benfica honoured their former coach Sven-Göran Erikssen who had led them to three national championships and into two European finals. Erikssen has revealed that he has terminal cancer.
