The A45 motorway near Münzenberg north of Frankfurt was completely shut down in both directions while rescue services tried to pick through the wreckage to reach those inside, some of whom had to be cut out.
Local catastrophe service spokesman Hagen Vetter said the autobahn looked like a battlefield, covered in wreckage.
Heavy drifting snow had already led to several accidents in the area before the massive crash.
Earlier in the day a school bus crashed head-on with a car in eastern Germany, killing both men in the vehicle and injuring 30 children.
The 55 children onboard were en route to their school in the small village of Salzwedel in Saxony-Anhalt, when their bus and a car collided.
Both men in the passenger vehicle died at the scene. According to the Süddeutsche Zeitung the driver came around a right-hand bend and into the wrong lane, where it hit the bus front-on.
A replacement bus was used to take the children to school, where they were seen to by doctors. Just one of them had to go to hospital.
Heavy snow and ice caused crashes all over Germany's roads over the past few days. Four people were injured in a pile up near Bornheim in North Rhine-Westphalia (NRW) on Monday evening, Der Spiegel magazine reported.
One driver died after his car hit black ice near Marburg, in the central state of Hesse. In NRW again, a woman lost control of her car and crashed into a tree. She and the passenger – her son – both had to be hospitalised.