"We are realistic and will have several dead to report at the end of the day," police spokesman Juergen Stadter told rolling news channel NTV.
There was "only a glimmer of hope" that 17 people missing after the collision would be found alive outside the coach, which was completely gutted, he added.
"Maybe someone ran away in shock," Stadter said.
Another police spokeswoman, Anne Hoefer, also told AFP that "it is completely possible that some people did not make it out of the bus, it's unclear where 17 of them are".
The crash shortly after 7 am (local time) sent the bus up in flames.
Some 31 injured people were pulled out of the bus, said Hoefer.
Images on television showed only a charred skeleton of the bus remaining.
It was unclear what kind of tour group the bus was carrying.
According to the Bild newspaper, the coach was travelling from the eastern region of Lausitz and heading for Nuremberg.
The accident struck near the town Bayreuth, which draws thousands of classical music lovers every summer to its opera festival.
An emergency team, including firefighters and rescue workers, were at the scene, while traffic on the motorway was halted in both directions.
Those hurt were being flown by rescue helicopters to hospitals, many with life-threatening injuries.
If those missing are confirmed killed, the accident at the start of the summer holiday season would be one of the worst to hit Germany.
Among the deadliest in recent years was a collision in June 2007, when 13 people were killed as their tour bus drove off the road and plunged several metres down a slope in eastern Germany's Saxony-Anhalt state.
Across Europe, the last such fatal accident struck on January 21 in Italy, when an accident involving a Hungarian bus carrying teenagers left 16 dead.
In France, a head-on crash in October 2015 between a truck and a bus carrying pensioners claimed 43 lives as both vehicles burst into flames.
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