Some of the victims have multiple gunshot wounds, according to police.
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Police said gunfire erupted just after 1:30 a.m. Tuesday near South Wells and Van Buren streets in the Loop.
Three victims, a man and two women, were inside a Dodge Durango stopped at a red light when two unknown men fired shots from the sidewalk, according to police.
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The driver of the Durango then drove to Stroger Hospital and dropped off the two female passengers for treatment. One of those women is in critical condition.
Then the driver left, police said.
Illinois State Police caught up with him in Maywood and found him with a critical gunshot injury from the shooting.
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Meanwhile, a 26-year-old woman who was crossing the street in the Loop was also hit by a bullet in her left leg. Police said she was in fair condition.
Police were also investigating a bullet hole in a nearby office building at 425 South Financial Place, but they have not confirmed if the damage is linked to the shooting.
"It's terrible to hear. It's shocking. The city is a great place to come and live and work, and we want peace," said Josh Schnurman, who works in the Loop.
People parking for work Tuesday morning near the scene are disappointed to hear about yet another violent incident downtown.
However, Brian Chadwick said he still feels safe coming into the Loop.
"It's safe during the day but at night, things change and, you know, the police presence in the city isn't what it once was," Chadwick said.
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This shooting comes just one day after Police Superintendent David Brown addressed crime in the city, including the downtown area.
"I'm hoping to start some of that deployment tomorrow and continue that through the rest of the month, and really through Labor Day, if not beyond," Brown said.
The mayor also promised to do everything she can to make people feel safe coming back to work downtown.
Reggie Guy, who commutes to the Loop for work, also said he feels comfortable.
"I actually feel safe coming downtown, I mean, I drive in from Indiana," he said. "I think overall, for the most part, it's pretty safe."
Police continue to search for the shooters and so far the motive remains unclear.