All New Yorkers will need to be vaccinated if they want to go to work, the city's mayor has announced.
Public sector employers already have to be inoculated, but the mandate will now be extended to all private sector employees, Bill de Blasio told MSNBC.
The policy will take effect on 27 December, he said.
"We in New York City have decided to use a pre-emptive strike," said Mr de Blasio, who leaves office at the end of December.
"We've got Omicron as a new factor, we've got the colder weather which is going to really create new challenges with the Delta variant, we've got holiday gatherings," he said.
"Vaccine mandates are the one thing that breaks through."
He said New York would be the first US city to mandate vaccines for private sector workers, affecting around 184,000 businesses.
A mandate for public sector workers which came into force earlier this autumn met vocal resistance, and led some employees to leave their jobs. However, rates of vaccination rose in response to the policy.
Ten cases of the new Omicron variant, which is thought to be more transmissable than previous strains of Covid, have been identified in New York City and the immediate surrounding region.
One person who tested positive for Omicron attended an anime convention in Manhattan on 23 November, mixing indoors with hundreds of other people.
Mr de Blasio said it should be assumed that there was already community spread of the variant in New York.
Rates of the virus in the city, at around 20 per 100,000, according to the New York Times' Covid data, is lower than the overall US average of 33 per 100,000, but has been rising over the past month,
Overall rates of vaccination across the US stand at 60% of the population. Around 69% of New Yorkers are fully vaccinated, although the rate varies widely between communities.
Mr de Blasio urged other US cities to follow his example.
"This would be my advice to mayors, governors, CEOs all over the country - use these vaccine mandates. The more universal they are, the more likely employees will say, OK it's time I'm going to do this, because you can't jump from one industry to another or one company to another. It's something that needs to be universal to protect all of us."
Mr de Blasio said he expected to receive cooperation from New York's business community, in the same way they had adopted and enforced vaccination requirements for eating indoors at restaurants, events and gyms. Further guidance on the new policy will be issued on 15 December.
President Biden's nationwide policy to mandate vaccines for the private sector has been stalled by opposition in Congress and the courts.
But dozens of private sector employers have already said staff must be vaccinated to return to office-based roles, from investment giants such as Morgan Stanley, Blackrock and Goldman Sachs, to the likes of McDonald's, Walgreens and Walmart.
Kathryn Wylde, president of the business organisation Partnership for New York City said the business community had been "blindsided" by the announcement.
"Inconsistent policies at the federal, state and city levels are not helpful and it is unclear who will enforce a mayoral mandate, and whether it is even legal," she said.
Joe Borelli, minority leader on New York City Council tweeted that he planned to mount a legal challenge to the plan.
We will have a lawsuit through our attorney partners ready to go as soon as the mandate is implemented, if not sooner. Just an fyi.— Joe Borelli (@JoeBorelliNYC) December 6, 2021
He said implementation of the policy would depend on the in-coming mayor Eric Adams.
In addition to the sweeping new mandate covering private employers, Mr de Blasio announced a toughening of the rules regulating entry to restaurants, bars and gyms.
Currently customers must prove they have received at least one dose of the vaccine. That will be changed to two, except for recipients of the one-dose Johnson & Johnson vaccine. Children under the age of 12 were previously exempt, but from 14 Dec will also be required to show proof of vaccination, now that the programme has been rolled out to include them.