Mesut Ozil will miss Germany's Euro 2016 qualifier against Poland on Saturday and faces up to 12 weeks out with a knee injury, the German Football Association (DFB) confirmed on Wednesday.
The 25-year-old Arsenal star complained of pain in his left knee and was flown to Munich on Wednesday morning to be treated by the DFB's doctor, who diagnosed a partial tear of the left cruciate knee ligament.
Ozil will miss the Group D qualifiers in Warsaw and against the Republic of Ireland in Gelsenkirchen next Tuesday.
He also misses a qualifier against minnows Gibraltar in Nuremberg on November 14, plus a friendly against European champions Spain on November 18.
Ozil is also added to Arsenal manager Arsene Wenger's mounting injury list and will miss the rest of the Gunners' Champions League group stage matches, including the key Group D showdown at home to Borussia Dortmund on November 26.
Germany coach Joachim Loew is already missing several stars for the trip to Warsaw with captain Bastian Schweinsteiger, Sami Khedira, Benedikt Hoewedes, Marco Reus and Mario Gomez all injured while midfielder Julian Draxler has the flu.
Chelsea forward Andre Schuerrle also missed training on Wednesday with a muscular problem, but is expected to be fit.
"Things look good for Andre, he received some treatment on Tuesday, so it's normal that he sat out training the day after," said team manager Oliver Bierhoff.
Draxler, of Schalke, is expected to join the squad once he recovers from illness.
Even without Ozil, Loew has targeted six points from their games against Poland and Ireland to give the Germans control of Group D after they beat Scotland 2-1 in their opening match.
Bierhoff said Germany are rebuilding after established stars Philipp Lahm, Per Mertesacker and Miroslav Klose all retired in the wake of their World Cup triumph in Brazil in July.
"We want to win both games and give ourselves a bit of a cushion in the qualifiers," added Bierhoff.
"It's going to be a tough October with two difficult games.
"We have to introduce several new players into the squad because of injuries and a few retirements.
"The team will have a different look to how it was two months ago."
With Schweinsteiger injured, Germany will be captained by goalkeeper Manuel Neuer for the next two games.
"These are key games for us, it is important to keep playing well after the win over Scotland," said Neuer, of Bayern Munich.
Loew is set to hand a first cap to Bayer Leverkusen attacking midfielder Karim Bellarabi, who has opted to play for Germany over Morocco, where his mother was born, on the back of several impressive displays in the Bundesliga.