Lyon extended their winless run in Ligue 1 to six matches after they suffered a 3-2 defeat at Stade Rennais in their first match under new coach Laurent Blanc on Sunday.
Martin Terrier scored twice for Rennes, who registered their third straight league win and moved two spots up to fifth in the standings on 21 points after 11 matches.
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Lyon, who appointed former France defender Blanc to replace Peter Bosz, have lost five of their last six games and slipped to 10th on 14 points.
Lyon took the lead in the 22nd minute when Alexandre Lacazette scored a header following a cross from Nicolas Tagliafico after Moussa Dembele started the move in the midfield.
But Rennes drew level in the 37th minute through Terrier, who scored a header against his former team following a brilliant aerial pass from Benjamin Bourigeaud.
Ex-Lyon player Amine Gouiri made it 2-1 for Rennes in the 46th minute with a low strike from close range as Lorenz Assignon found him with a delightful cross.
Lacazette tapped home the equaliser in the 71st minute, scoring his sixth goal of the season but Terrier made it 3-2 for the hosts five minutes later with a powerful header, sending the crowd at Roazhon Park into a frenzy.
Earlier, 2020-21 Ligue 1 champions Lyon suffered a blow before halftime when midfielder Corentin Tolisso was forced off the field with a suspected thigh injury.