A new protest party led by former comedian Beppe Grillo, who is calling for a referendum on the euro, is also set to make major gains as Italians endure their longest recession in two decades and the heavy burden of austerity cuts.
Polling stations open at 0600 GMT and close at 1400 GMT, after which exit polls and early official results are expected later on Monday and into Tuesday.
Democratic Party leader Pier Luigi Bersani has said he is the best man to help promote a growth agenda for Europe and "turn the page" after years of Silvio Berlusconi, who polls indicate could come second in the vote.
Billionaire and three-time prime minister Berlusconi has waged a populist campaign, blaming Germany for Italy's economic woes and promising to refund an unpopular property tax to Italians -- out of his own pocket if needed.
European capitals are watching closely for any signs of fresh political instability in the eurozone's third economy that could send shockwaves through the euro area or a return to the bad old days of free-wheeling public finances.
Bersani has said he will abide by the budget discipline enforced by outgoing prime minister Mario Monti, a former European commissioner roped in after Berlusconi's ouster in 2011 who has done much to reassure financial markets.
But the former communist turned liberal economic reformer Bersani will face pressure from trade unions and many ordinary Italians who have seen unemployment rise to record highs and the economy spiral downwards.
"I don't want us to end up like Greece," said Alessandro, a 63-year-old manager, as he voted in Milan. Daniele, 47, a disgruntled taxi driver, said: "The whole political system is rotten. This will be a wake-up call."
The down-to-earth Bersani, 61, the son of a car mechanic from northern Italy, has struggled to overcome his image as a party apparatchik and has surrounded himself with a youthful team with many women in the ranks.
The wild card will be the tousle-haired Grillo, who has spoken to packed squares across Italy during the campaign, drawing the crowds with his mixture of invective against traditional politicians and grassroots idealism.
"They are attacking us, they're terrorised, because we're doing something exceptional. We are actually going to win the election!" he said earlier during a trip to Lombardy, the biggest region and a Berlusconi stronghold, making it a key election battleground.
Grillo built up the suspense on Sunday over when he would come out and vote and was expected to do so on Monday, while Berlusconi was mobbed by three topless feminists in a protest as he arrived to cast his ballot on Sunday.
The 76-year-old media tycoon has survived multiple scandals in 20 years in politics and is a defendant in two ongoing trials -- one for tax fraud and the other for having sex with an underage prostitute and abuse of power.
The most recent polls indicate that Bersani will win easily in the lower house of parliament but will fail to garner a majority in the upper house, meaning he will have to weave together a coalition in order to govern.
This could mean an alliance with the economics professor Monti, who is expected to come in fourth place. A partnership between the free-marketeer Monti and radical leftists who support Bersani could be uneasy, analysts warn.
Politics professor Roberto D'Alimonte has said these elections are the most important in Italy since the early 1990s -- when a series of corruption scandals brought down a political order dominated by the Christian Democrats.
"In 1994, the consequences were only about us. That is not the case anymore; now they are about Europe and its future," D'Alimonte said.