The Foreign Ministry said the referendum was held in line with democratic principles.
According to the official results of the referendum, held in conjunction with the self-declared republic's presidential election, 99% of voters backed independence, while 96% voted for incumbent leader Eduard Kokoity.
The ministry said in a statement released late Monday evening, "Whether people like it or not, we are dealing here with an expression of free will by the people of South Ossetia, expressed through democratic procedures."
"No matter how Georgia or several other Western countries try to dismiss the importance of this event, it is nevertheless significant. To ignore this is, to say the least, short-sighted."
South Ossetia declared its independence from Georgia following a bloody conflict in 1991-1992 that killed hundreds of people. The incumbent Georgian leadership is determined to bring the breakaway region back under its control, and accuses Russia of backing separatists in the region, a charge that Moscow denies.
Russia, which remains entangled in a furious diplomatic dispute with Georgia, has stressed ex-Soviet breakaway regions' right to decide their own fate, and compares them to Kosovo's drive for independence from Serbia.
After the referendum, the European Union said it did not recognize the vote, and supported Georgia's integrity within existing borders.
The Foreign Ministry said the results of an 'alternative election' held in Georgian villages in South Ossetia on Sunday were doubtful.
"As far as the 'alternative' election is concerned, as we predicted earlier the figures in the announced results are beyond the largest expectations. One can only guess how the organizers of this show managed to gather more than 40,000 voters simultaneously in several villages."
South Ossetia, which seceded from Georgia after the collapse of the Soviet Union and a bloody conflict with Tbilisi in 1991, previously held referendums, aiming to gain international recognition of its independent status, in 1992 and in 2001; both referendums failed to achieve this goal.
The breakaway region has also stated its desire to join the neighboring Russian republic of North Ossetia, with which it is ethnically and historically connected. The majority of people in South Ossetia already hold Russian passports, and the Russian ruble is widely used.