Novak Djokovic lost serve five times in a 6-3, 4-6, 6-2 defeat by Russia's 10th seed Daniil Medvedev.
Marin Cilic suffered a shock Wimbledon second round exit as last year's runner-up blew a two-set lead in his 3-6, 1-6, 6-4, 7-6 (7/3), 7-5 loss to Argentina's Guido Pella on Thursday.
Defending champion Marin Cilic defeated Argentine qualifier Guido Pella 6-3, 7-6 (7/3), 7-6 (7/3).
Djokovic has won every Grand Slam title except the French Open and has made this year's tournament his priority. The Serb lost last year's rain-interrupted final at Roland Garros to Spaniard Rafael Nadal.