That put him ahead of Giancarlo Cancelleri of the populist Five Star Movement (M5S), who was projected to have taken 35.1 percent and 36 percent by the pollsters.
Only around 46 percent of the 4.5 million eligible voters were projected to have turned out to vote, slightly down from other recent votes on the mafia-plagued island where disillusionment with politicians runs deep.
The leading margin remained too small for the favourite to declare victory but Giorgia Meloni, leader of one of the small right-wing parties in alliance with Berlusconi's Forza Italia, said "it seems pretty clear Nello Musumeci has won".
That would represent a setback for Five Star, which had harboured ambitions of taking control of its first region after claiming the mayorships of Rome, Turin and a string of smaller municipalities last year.
Five Star did double its popular vote from the last round of regional elections and claimed a moral victory on the grounds that it was projected to get more votes that any other single party. Fabrizio Micari, the candidate of Italy's ruling Democratic Party (PD), was expected to claim around 20 percent of the vote having suffered less slippage than expected to a rival from the far left.
PD regional secretary Fausto Raciti warned that the vote had worrying implications for the Italian left as a whole. "As we wait for the definitive results, we can only recognize a clear defeat. I hope that this outcome will trigger reflection across the left on the need for unity," he said.
As things stand, the PD will enter the general election, which must take place in the first half of 2018, with former premier Matteo Renzi as its candidate to lead the country. A centrist, Renzi is loathed by many on the left of his own party and in other factions. They accuse him of adopting right-wing policies in the guise of reforms aimed at bolstering Italy's flagging competitiveness.
Renzi also carries the baggage of his defeat in a 2015 referendum on constitutional reform that led to his resignation and replacement by current premier Paolo Gentiloni.
Barred from office
In contrast, Berlusconi is on the rise again and victory in Sicily will strengthen the 81-year-old's hand as he prepares to tie down the terms of a general election alliance with the far-right Northern League.
"This marks the start of a wonderful new chapter for the united right," said Giovanni Toti, governor of the northern region of Liguria and a key lieutenant of the revitalized Berlusconi.
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The four-time former premier had been written off as a spent political force after a series of scandals and open heart surgery last year. He is barred from public office as a result of a conviction for tax fraud, but is hoping to have the ban lifted. Even if it is not he will be a central figure in what promises to be a highly unpredictable election.
With the left struggling to overcome its divisions and M5S losing momentum, a Forza Italia-Northern League alliance looks well-placed to emerge as the biggest force at the polls, which will be fought under a new electoral system favouring broad alliances.
M5S has denounced the electoral reform as rigged against it. The party, which styles itself as an anti-establishment force, has thus far ruled out entering into any alliance.
Its candidate for prime minister, Luigi Di Maio, had been due to debate Renzi on national television on Monday but pulled out as the disappointing Sicily results emerged.
By Angus MacKinnon