M5S is the largest party in Prime Minister Giuseppe Conte's coalition government, and Luigi Di Maio's exit could further weaken an already fragile alliance with the centre-left Democratic Party (PD).

Di Maio, 33, announced his resignation at a party meeting in the afternoon, Italian newspapers said.

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Luigi Di Maio, leader of the Five Star Movement and Foreign Minister. Photo: Andreas Solaro/AFP

It comes days ahead of a key regional poll pitting the M5S and PD against Matteo Salvini's rightwing populist opposition party, the League.

The League, which enjoys a significant lead in national polls, hopes that defeating the M5S and PD on Sunday in Emilia Romagna — a historic heartland of the left — will spark a crisis and bring down the government.

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A League victory would increase tensions considerably, with the PD likely to blame the M5S for refusing to join forces behind a single candidate — thus splitting the anti-Salvini vote. The governing coalition's main stabilising factor is a joint fear of snap elections which could hand power to Salvini.

The M5S was likely to perform particularly badly, according to the last polls ahead of the ballot.

Di Maio was expected to remain foreign minister, but reportedly told relatives “this is the time to take a step back, I am exhausted,” online Italian newspaper TIP said.

He has been head of the M5S since September 2017, but has faced mounting internal dissent as the movement loses popularity and lawmakers abandon it. Two more lawmakers said Tuesday they were quitting the party, which has haemorrhaged over 15 members since forming the coalition with the PD in September.

Senator Vito Crimi was slated to temporarily take over as chief ahead of a party conference due in March.

“This is a delicate moment for the M5S. We have to go forwards united, because if we split we condemn ourselves to irrelevance,” M5S minister Vincenzo Spadafora told reporters on Wednesday.

Co-founded by comedian Beppe Grillo, the movement initially claimed to be neither right nor left wing but the only “honest” alternative to establishment parties.

It initially refused any alliances. But March 2018 elections saw it become the biggest party in Italian politics with 32 percent of the vote, and the M5S eventually formed a relatively short-lived coalition with Salvini's League, before that ended and it joined forces with the PD.

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Telegenic Di Maio is credited by supporters with turning M5S into a mainstream political force capable of allying with right and left, but critics have long derided him as a self-centred robot.

The Movement's popularity plummeted during its time with the League, and has struggled to recover. Some within M5S have called for the party to be restructured, saying the leader currently has too much power.

Political experts say the apparent ease with which the M5S swapped a marriage of convenience with the League for one with the PD has inevitably lead to fierce internal bickering.

“The Five Stars do not know what they are,” commentator Claudio Tito wrote in the Repubblica daily on Tuesday. “They are jerked this way and that by a constant oscillation between sovereignty and welfarism, between populism and moralism, between a visionary idea of the future and attachment to their political thrones.”