Hundreds of people are sailing to Spain on the first passenger ferry crossing from Plymouth in eight months.
Operator Brittany Ferries said most of the 800 passengers will be vaccinated or second home owners travelling to check on their properties.
The Pont-Aven, which can accommodate up to 2,400 passengers and 650 cars, departed at 16:45 BST on Sunday.
Nigel Wonnacott, from Brittany Ferries, said: "We are very excited and I know they are too."
Spain is currently amber according to the government's traffic light system for foreign travel, whereby countries are classed as green, amber or red - with different rules for quarantine and Covid tests.
Asked about Prime Minister Boris Johnsons's advice that people should not be holidaying in amber list countries, Mr Wonnacott said most passengers were second home owners who would say they believed it was essential to travel to check on their properties.
He said some passengers were taking a "rather more Stanley Johnson approach to the rules", which was to look at the risks and say they were vaccinated and the areas they were travelling to were low-risk in terms of the prevalence of infections.
Waiting to embark in Plymouth, Frank Barrett, from near Macclesfield, said he would be in Spain for six weeks so there was a chance the country's designation would change but he was not worried about it being an amber list country.
"We are taking all the precautions we can," he said.
John and Diana Hayward, from Surrey, said they would be driving straight to Portugal, where they would stay for 90 days when they arrived in Santander, while Christine Heath, from Southport, said she going to see her daughter and 10-month-old grandson.
"I'm willing to go home and isolate as long as I can see my family," she said.
Mr Wonnacott added: "It's been a very tough time for the company and for our passengers ... we are delighted to be back."