A man opened fire at about 04:30 (01:30 GMT) on Sunday, killing one person. The gunman was then shot and injured by police and died later in hospital.
The attack unfolded at the Grey club on Max-Stromeyer-Strasse.
Multiple German reports said the second person killed was a guest at the club.
Others were able to save themselves by fleeing outside or hiding, police said.
A doorman appeared to have been shot with an automatic pistol as he tried to stop the attacker, witnesses told broadcaster SWR.
One police officer was also wounded in the exchange of fire. The officer’s injuries are not thought to be life-threatening.
Police and prosecutors said in a statement (in German) that special commando forces and a police helicopter had been deployed in the city, as it was not yet known if the suspect had accomplices.
The motive for the shooting is not immediately clear.
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