Controversially, no women have been selected for the experiment, called Mars 500.
Dressed in blue overalls, the men gave the thumbs-up sign and smiled for the cameras as family members and well-wishers gave them an emotional send-off before they entered the facility.
"See you in 520 days," shouted one Russian, Sukhrob Kamolov, just before a scientist shut the door on the facility and sealed it shut at around 10:00 GMT.
Like in a real Mars mission, the crew will have to survive on limited food rations like those used by real astronauts, and their only communication with the outside world will be by email, with a delay of up to 40 minutes.
The hatch will only re-open when the experiment is over, or if one of the participants is forced to pull out.
The volunteers are aged between 27 and 38 and include a member of a real-life space programme and a civil engineer.
The volunteers will have their days in the module at the Russian Institute for Biomedical Problems (IBMP) divided into eight hours of sleep, eight hours of work and eight hours of leisure.
A team of three will spend one month aboard a special module meant to represent the Mars landing craft, while two will also spend time exploring a reconstruction of Mars itself.
Chinese member Wang Yue, 27, a candidate astronaut of China's space programme, told reporters before entering the capsule: "It is just a simulation. It is not a matter of life and death."
"But I think it is very much more than that as it aims at the future of humanity."
The idea is to exactly mimic the timescale of a Mars mission. This includes 250 days for the trip to Mars, 30 days on the surface and 240 days for the return journey.
The ESA and the US space agency NASA have separately sketched dates in around three decades from now for a manned flight to Mars.
The project, the first full-duration simulated mission to Mars, follows a similar experiment in Moscow last year which saw six volunteers shut away for 105 days.