It happened just before 11:30 p.m. Wednesday on the 900 block of East Locust Avenue in the East Germantown section of the city.
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Officers on patrol in the area came upon the altercation, which police also called a fight.
When the officers exited their vehicle, they found the victim lying on the street suffering from a stab wound to the chest.
The 42-year-old man was taken to the hospital where he was pronounced dead.
Police located a 16-year-old male suspect at the scene.
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The teen was taken into custody for questioning by homicide detectives.
"At this time, we believe the 16-year-old perpetrator does know this 42-year-old victim. We believe the motive may be domestic-related," Philadelphia Chief Inspector Scott Small said.
Police confiscated a knife found near the victim.