Hundreds of DVLA staff at the agency's site in Swansea will begin a four-day strike on Tuesday over Covid-related safety.
Members of the Public and Commercial Services (PCS) union will walk out until Friday after failed talks to resolve the dispute.
The union wants to see changes to the way the site is operated during the ongoing pandemic, like a further reduction in the number of staff working in the offices.
A coronavirus outbreak was declared at the DVLA's contact centre in Swansea in December 2020. By the end of February this year, 560 Covid cases had been recorded amongst DVLA employees - working on site and from home - since September.
The DVLA said it has followed official health guidance for keeping staff safe. It said in a statement it has had no new confirmed cases since the 24 March in the company which employs more than 6,000 people.
The union said the strike will include staff who have been working on site.
Further industrial action is threatened if managers do not make the safety improvements the union is demanding.
The PCS said progress had been made in talks but the lack of immediate moves to reduce numbers on site means the strike will go ahead.
Agreement had been reached on removing more than 300 desks, revising risk assessments - which has led to a further 300 staff being sent home - and a commitment on how to go forward with talks over the coming months.
The PCS described the DVLA workplace as "clearly not safe" and called on the agency to "enter into meaningful negotiations with the union".
PCS General Secretary Mark Serwotka said: "That PCS members are prepared to take unprecedented strike action shows just how badly DVLA management have failed in their responsibility to keep staff safe.
"No civil servant should have to go on strike to guarantee their safety at work.
"We are determined to only send our members back into DVLA when the workplace is safe again."
A DVLA spokesman said, "The safety of our staff is paramount, and we have continuously adapted our measures over the past year and will continue to do so. There is currently not a single member of staff in the 10 day isolation period, our of a workforce of more than 6,000."
The DVLA said the strikes were likely to delay paper applications it receives as well as calls to its contact centre, but online services will still be available.