CPD said an employee found the safe was empty about 9:55 a.m. Monday.
The bank, located at 2163 N. Clybourn Ave., had been closed over the weekend, and the safe was also closed, with money inside, at the time, CPD said.
Police said forced entry had been made through an adjacent building.
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ABC7 Chicago cameras captured wood appearing to cover something up behind the bank, and a "temporarily closed" sign at the bank's front entrance Tuesday morning.
The FBI and Chicago police Area Three detectives are investigating the incident.
No one was in custody as of Tuesday morning.
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