The two victims were climbing out of a white Mercedes SUV on Friedrich-Stoltze-Platz in the late afternoon when the attackers opened fire.
They had been sitting outside a cafe just metres away from the Zeil pedestrian zone, one of Germany's busiest shopping streets.
Large numbers of heavily-armed officers were immediately dispatched to the scene, where the victims' car could be seen standing with several bullet holes in its windscreen.
Officers are now hunting for a black estate car which they believe to have been the getaway vehicle.
A pistol lies on the ground at the scene of the shootout in Frankfurt. Photo: DPA
A motorbike and a firearm were both recovered from the scene and have been taken in for forensic tests.
Investigators told the Frankfurter Allgemeine Zeitung that they had ruled out the possibility of a terrorist attack and were focusing on possible links to organized crime.