Italy's government crumbled when three of Prime Minister Mario Draghi's main coalition partners snubbed a confidence vote he had called to try to end divisions and renew their alliance.
Mr Draghi won the vote in the upper house by 95 to 38 but with many dozens of senators absenting themselves, leaving his 18-month-old administration in tatters with an early election in September or October the most likely outcome.
On the right, Forza Italia and the League parties did not take part in the vote.
They were joined by the populist 5-Star Movement which also shunned the vote, having set off Italy's latest political crisis with a similar boycott last week.
Mr Draghi had tendered his resignation last week, but President Sergio Mattarella turned him down and told him to go before parliament to see if he could revive the broad coalition.
Mr Draghi had earlier made a plea for unity and set out a series of issues facing Italy ranging from the war in Ukraine to social inequality and rising prices.
"The only way, if we want to stay together, is to rebuild this pact, with courage, altruism and credibility," Mr Draghi said in an uncompromising speech to the Senate, adding that many Italians wanted the coalition to carry on until elections due early next year.
The crisis comes at a tough time for debt-laden Italy, the third largest economy in the eurozone, where borrowing costs have risen sharply as the European Central Bank starts tightening its monetary policy.
European Economy Commissioner Paolo Gentiloni said on Twitter that the "irresponsible" move against Mr Draghi could lead to a "perfect storm" and "difficult months ahead" for Italy.
The head of Italy's centre-left Democratic Party (PD), another coalition party, said parliament had gone against the will of the people.
"Italians will show themselves to be wiser at the ballot box than their politicians," PD chief Enrico Letta wrote on Twitter.