The yellow school bus crashed into a car before careening head-on into the side of the city bus, which was carrying morning commuters.
"This was a major incident, some seasoned individuals in my organization said they haven't seen this type of wreck in their career," Baltimore Fire Department Chief Niles Ford told a press conference.
Images and video from the scene showed the school bus's front end crumpled and lodged in the commuter bus's flank, which it ripped open.
An additional 10 people were taken to area hospitals for injures which ranged "from minor to critical," Smith said.
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Those injured included eight people on the city bus, plus an aide who had been the only passenger on the school bus. In addition, one person from the initial car crash was injured.
Police said the bus hit the car, a Ford Mustang, in the rear before striking a pillar at a nearby cemetery and then careening into oncoming traffic, hitting the commuter bus.
"There aren't any skid marks. So something catastrophic took place and it's something we're continuing to investigate," he added.
The bus had been en route to pick up a student about four or five blocks away, he said.
"It literally looks like a bomb exploded in the bus and it's catastrophic damage," Smith said.
Additional assistance, including from investigators in the city's homicide unit, have been brought in, Smith said, emphasizing that no criminal investigation was under way.