American companies with more than 100 employees must ensure their staff are vaccinated against coronavirus or tested weekly, President Joe Biden has said.
He has also tightened the rules for federal employees, saying they have 75 days to get vaccinated. If not, their employment could be terminated unless they are exempt.
Previously, they had a choice between vaccination and testing.
In addition, more than 17 million healthcare workers involved in Medicare and Medicaid programmes for the disadvantaged are being urged to make sure they are immunised against COVID-19.
The new measures will cover around two thirds of all US employees, amounting to about 100m people.
Mr Biden justified his action by saying the US is in a “tough stretch and it could last for a while”, adding: “We can and will turn the tide on COVID-19.”
Speaking at the White House, President Biden said the unvaccinated minority “can cause a lot of damage, and they are”.
He added: “We’ve been patient. But our patience is wearing thin, and your refusal has cost all of us.”
The Labor Department’s Occupational Safety and Health Administration will issue a rule for private companies in the coming weeks.
Those that do not comply could face fines of almost $14,000 (£10,100) per violation.
The Biden administration also plans to increase testing.
Some 80m US citizens have still not been vaccinated. “Our overarching objective here is to reduce the number of
unvaccinated Americans,” White House spokeswoman Jen Psaki said.
“We want to reduce that number, decrease hospitalisations and deaths and allow our children to go to school safely.”
According to data from the US Centers for Disease Control, just over 53% of Americans are fully vaccinated.
Jim Worthington, who owns an athletic club in Bucks County, Pennsylvania, which has several hundred employees, said the new rules put him in an “awkward position”.
“I am pro-vaccine, but also pro-people’s rights,” he said. “It would really depend on what they do if we don’t comply. Are they shutting us down?”
The American Federation of Government Employees said “changes like this should be negotiated with our bargaining units where appropriate”.
It added: “Put simply, workers deserve a voice in their working conditions. Neither of these positions has changed. We expect to bargain over this change prior to implementation, and we urge everyone who is able to get vaccinated as soon as they can do so.”