The shooting happened just after midnight near the Greyhound bus stop at 2121 Main Street near Webster Street.
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Two men were shot and the suspect fled on foot, Houston police said.
One person was detained at the scene, but it's unclear if he pulled the trigger.
The first victim, who was around 35 years old, was taken to the hospital, where he was later pronounced dead.
Police said another man, who is in his 50s, was shot in the hand and was also taken to the hospital.
HPD said the second victim was actually asleep at the time, so he didn't see what happened and didn't have a description of the shooter.
Investigators said it's unclear what exactly led up to the shooting and if it was random or targeted.
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"All we know is that we had two individuals shot. We had several calls that came into the dispatcher that provided descriptions of individuals, but all of the descriptions were different," Cmdr. Caroleta Johnson said.
Police said the man who was detained at the scene loosely met the description that was provided by one of the witnesses, though his involvement in what happened was unknown.
Investigators were reviewing surveillance video in the area.
Anyone with information about what happened is urged to call HPD's homicide division at 713-308-3600.
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