The US Supreme Court has blocked President Joe Biden's rule requiring workers at large companies to be vaccinated or masked and tested weekly.
The justices at the nation's highest court said the mandate exceeded the Biden administration's authority.
Separately they ruled that a more limited vaccine mandate could stand for staff at government-funded healthcare facilities.
The administration said the mandates would help fight the pandemic.
President Biden, whose approval rating has been sagging, expressed disappointment with the decision "to block common-sense life-saving requirements for employees".
He added: "I call on business leaders to immediately join those who have already stepped up - including one third of Fortune 100 companies - and institute vaccination requirements to protect their workers, customers, and communities."
Former President Donald Trump cheered the court's decision, and said vaccine mandates "would have further destroyed the economy".
"We are proud of the Supreme Court for not backing down," he said in a statement. "No mandates!"
The administration's workplace vaccine mandate would have required workers to receive a Covid-19 shot, or be masked and tested weekly at their own expense.
It would have applied to workplaces with at least 100 employees and affected some 84 million workers. It was designed to be enforced by employers.
Opponents, including several Republican states and some business groups, said the administration was over-stepping its power with the requirements, which were introduced in November and immediately drew legal challenges.
In the end, Joe Biden's vaccine mandates stood or fell based on judicial interpretations of federal statute, not principles of individual liberty or appeals to the greater good.
According to a majority of the Supreme Court, Mr Biden had the law on his side when ordering healthcare workers to get vaccinated, but using a 51-year-old workplace safety statute to implement a vaccine-or-test requirement on all large employers was a bridge too far.
Once again, the current balance of the Supreme Court comes into sharp relief, with four reliably conservative justices, three reliable liberal ones and two - Chief Justice John Roberts and Justice Brett Kavanaugh - at the ideological fulcrum.
This mixed judicial bag is just the latest setback for a presidential Covid-response plan that frequently has seemed a step behind the latest twists in the pandemic. The administration was slow to encourage boosters and caught flat-footed by the Omicron-induced surge in demand for testing.
Now Mr Biden will either have to convince Congress to act on mandates - an unlikely prospect given the brick wall the rest of his agenda keeps hitting in the Senate - or figure out new ways to shepherd the nation out of the pandemic gloom.