Police said the crash happened in the Ukrainian Village neighborhood at West Chicago Avenue and North Damen Avenue just before 10:30 a.m.
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A 69-year-old man was driving a yellow Ford sedan westbound when he ran a red light, striking a 46-year-old man and 47-year-old woman, police said.
Witnesses said the impact sent the woman head-first into the car's windshield while the man was flipped into the air and landed on the vehicle's roof.
"He hit the guy, and tried to skip the guy, but hit the lady at the same time," said Carlos, a witness.
Police said the victims were transported to Stroger Hospital, where they are listed in serious condition. The driver was transported to the same hospital, where he is listed in good condition for unknown injuries.
"It's bad. You see the skid mark here. How fast we they going, that they leave this big of a slamming on the brakes?" said neighborhood resident Kevin Jandrists.
Some of those who live and work near the intersection are saddened, but not surprised to learn of the crash.
"You really just have to be extra careful, because you really can't expect anyone to drive safely, sadly," said Christopher Hooker, another neighborhood resident.
Michael VanDam, another resident, also weighed in.
"People run the red light here all the time. I think, at the very least, we need red light cameras here, and potentially other traffic-calming devices," VanDam said.
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Citations are pending and CPD's Major Accidents Unit is investigating, police said.
Police did not immediately provide further information about the crash.