The first victim was a 58-year-old woman who had contact with the original case, a South Korean who visited the Middle East.
A 71-year-old man also died.
The vast majority of cases have been in Saudi Arabia and other Middle Eastern countries, but South Korea has reported 17 since last month.
More than 680 people, who may have come into contact with the infected patients, have been placed in isolation.
Health ministry official Kwon Jun-wook told reporters on Monday that those in quarantine were being held at their homes or in state-run facilities in order to prevent the spread of the virus.
The first fatality from Mers was recorded in June 2012 in Saudi Arabia.
It belongs to the family of coronaviruses that includes the common cold and Sars, and can cause fever, breathing problems, pneumonia and kidney failure.
Experts believe the virus is not very contagious.
There have been 1,167 cases of Mers worldwide, of which 479 have died, according to the European Centre for Disease Prevention and Control.
The only previous fatality in East Asia was a Malaysian man who died in April after returning from a pilgrimage to Saudi Arabia.
Meanwhile nurses at a hospital in China have been reportedly drawing lots to determine who should treat the country's first case of Mers.
The hospital, in the southern city of Huizhou, said the ballot was arranged because there were too many volunteers to treat the South Korean man.
But posts on social media suggest many were reluctant to take on the task.
The virus has a death rate of 27%, according to the World Health Organization.
Two people have died of Middle East Respiratory Syndrome (Mers) in South Korea, becoming the country's first fatalities from the disease.