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Prime Minister Valeriu Strelet has been in office for less than three months.
The vote, triggered by socialist and communist opposition MPs, followed months of big anti-corruption protests.
Many Moldovans are furious over the disappearance of more than $1bn (£646m) from Moldovan banks. The protesters are demanding early elections.
A former prime minister, Vlad Filat, was detained earlier this month over his alleged involvement in the bank fraud - an allegation he denies.
The no-confidence motion was backed by 65 lawmakers in the 101-seat legislature.
Moldova is one of Europe's poorest countries. The missing money is equivalent to an eighth of the ex-Soviet republic's entire GDP.
The scandal caused a rapid fall in the value of the national currency, the leu, hitting Moldovans' living standards