Greek Defense Minister Panos Kammenos announced his resignation ahead of a parliamentary vote to ratify a deal ending a decades-old name dispute with Macedonia.
"The Macedonia issue does not allow me not to sacrifice my post," Kammenos said on January 13 following talks with Greek Prime Minister Alexis Tsipras.
He also said that his right-wing populist Independent Greeks (ANEL) party was quitting the government.
Tsipras later said he will ask for a vote of confidence in parliament in the coming week.
Kammenos has long opposed the accord signed by the Greek and Macedonian governments in June 2018.
The deal would change the name of Greece's northern neighbor to the Republic of North Macedonia. In exchange, Athens would lift its objections to the former Yugoslav republic joining NATO and the European Union.
Macedonia's parliament voted on January 11 to ratify changes to the constitution called for in connection with the agreement, which now needs backing from the Greek lawmakers to come into effect.
The deal has met with opposition in both countries with critics saying it makes too many concessions to the other side.
Athens argues that use of the term "Macedonia" implies territorial claims on Greece’s northern province of the same name, and on its ancient Greek heritage.
In a parliamentary session on January 11, 81 Macedonian deputies in the 120-seat parliament voted in favor of the proposed changes to the country's constitution, securing the required two-thirds majority.
It came after three days of negotiations between Prime Minister Zoran Zaev and lawmakers that opposed the changes.
Zaev said on January 12 that the lawmakers had "made history," adding: "I know how difficult that was. ... We are putting the bitterness in the past and we are looking now proudly to the future."
Greece's 300-member parliament needs a simple majority for ratification.
Tsipras has said that the chamber would be asked to ratify the agreement with Macedonia by the end of the month.
His left-wing Syriza party has 145 deputies in the legislature, and the prime minister may need votes from opposition lawmakers to pass the deal.