Calls came in around 2:15 p.m. for smoke coming from the former Junior High School #1, which later became the Martin Luther King Jr. School.
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Chopper 6 was over the scene at Southard St. and Martin Luther King Jr. Blvd. as flames engulfed the property.
Chopper 6 video of fire at vacant school in Trenton, New Jersey
Firefighters eventually struck at least three alarms.
Some homes along Evans Ave. were damaged by flying embers.
Shantae Ford says the top two floors of her home are badly damaged by the fire. In one room, her daughter had equipment in storage for a new business.
"Now I'm going to have to go out here get me a hotel for right now and find me another place to stay," said Ford.
A few doors up another neighbor had part of his back deck catch fire. He's one of many who say they have to leave for at least a night.
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"My daughter has asthma, my mother-in-law has breathing problems," said Shakur Smith of Trenton.
Residents say the school, which sat vacant for 20 years, should have been torn down a long time ago.
"They should have been doing something with that school a long time ago. And this is what we got right here today," said Derrick Smith of Trenton.
According to Mayor Reed Gusciora, the building was under the control of the Trenton Board Of Education and there were tentative plans for it to be turned into senior housing.
No injuries were reported.
The cause of the fire remains under investigation.