"City employees are absolutely going to be required to be vaccinated," Lightfoot said during a press conference Monday afternoon.
The announcement came hours after the FDA announced the Pfizer COVID-19 vaccine had been granted full approval in the United States.
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Lightfoot added that the city has been working with labor unions over the last several weeks to finalize plans. A formal announcement is expected as early as this week.
"We absolutely have to have a vaccine mandate," Lightfoot added. "It's for the safety of all involved, particularly members of the public who are interacting with city employees on a daily basis. It's important for colleagues to also feel like they have a workplace that's safe."
The city government is Chicago's third largest employer, with a workforce of more than 30,000 people.
More companies and hospitals are moving ahead with vaccine mandates with the number of COVID cases on the rise particularly with the more contagious delta variant. But already, some unions are digging in their heels.
"We are not just going to roll over and play dead for the mayor," said John Catanzara Jr., president of Chicago's Fraternal Order of Police. "She's not going to force it down our throats without a fight. And we will take it to the courts if necessary."
Catanzara said the four police unions will be meeting with City Hall Tuesday afternoon to discuss the mandate. The Fraternal Order of Police said this was not part of the recently negotiated contract for the rank and file.
"And we thought we had an understanding that we were perfectly fine with the option for our members to decide for themselves without it being a mandate," Catanzara added.
Lightfoot's office said the announcement would be made in the days ahead, but would not provide any details of the plan, or whether it would cover all or only certain city workers.
A spokesperson for the Chicago Federation of Labor said in a written statement: "Discussions regarding COVID-19 vaccinations are ongoing with the city. We appreciate the City's willingness to not announce a specific policy while those discussions continue."
A survey shows 13% of U.S. employers plan to mandate the vaccine, up from less than 3% in early July.
"Just in the last two or three weeks, the dam really broke on that," said Andy Challenger, senior vice president at Challenger, Gray & Christmas. "And that certainly gives a lot of cover to organizations around the country."