The ruling 5-Star Movement party in Italy said it will not participate in a confidence vote called by Prime Minister Mario Draghi later on Wednesday.
The League and Forza Italia centre-right parties have also announced that they will snub the motion, making it highly likely that Draghi will resign later in the day.
The confidence motion passed with 95 votes in favor and 38 against it: a weak and unacceptable outcome for Draghi, who in his Senate speech had earlier issued a call for national unity as a condition for staying in place.
The embattled premier is now expected to meet President Sergio Mattarella on Thursday morning and tender his resignation again. Mattarella had rejected Draghi's first offer to resign last week, asking him to assess the political situation in parliament.
Now, the president will not be left with many alternative options. The most likely decision would be to dissolve chambers and call early elections, most probably in early October.
Draghi made clear in his Senate speech that he was willing to stay in his role only if the parties in his broad coalition threw their full support behind his leadership.
He highlighted the challenges that Italy is facing, naming the war in Ukraine, soaring inflation, the energy crisis, and widening social inequalities.
His call for a new "pact" between the litigious partners of his right-left coalition, however, crashed against the conflicting requests of the parties and their crossed vetoes.
The end of Draghi's 18-month-long government deals a blow to Italy's credibility among international investors and risks to unsettle financial markets.
The new phase of political uncertainty comes at a crucial time for the highly-indebted country, which needs to meet the necessary conditions to receive its €200 billion share of the EU's recovery fund.