Prime Minister Binyamin Netanyahu left for Rome on Sunday for a two-day official visit during which he will meet Pope Francis for the first time.
Netanyahu took off around midday accompanied by six of his ministers, including Foreign Minister Avigdor Liberman, according to AFP.
During the visit, Netanyahu would also meet with his Italian counterpart Enrico Letta, and hold a joint session with the Italian cabinet.
On Monday, he will be granted his first audience with Pope Francis, who took over as the worldwide head of the Catholic Church in March.
Six weeks ago, Netanyahu's office had said he would meet the pope during a visit to Rome in late October, but the meeting never happened -- with a diplomatic source telling AFP it would not happen because it had not been coordinated in advance with the Vatican.
When the two meet on Monday, they are likely to discuss the Iranian nuclear issue and the ongoing peace talks with the Palestinian Authority. They are also likely to discuss the pope's alleged planned visit to the Holy Land early next year, which has been reported by Channel 2 but not confirmed.
Pope Francis has already been invited to visit the Christian holy sites by President Shimon Peres in April, and by Palestinian Authority Chairman Mahmoud Abbas, who met him on October 17.
Israeli sources say the visit is likely to take place before Peres ends his term as president in July. Although no date has been made official, sources on both sides say it is likely to take place on May 25-26.
The papal visit will reportedly begin in Jordan, a senior Vatican official said on Saturday, according to Jordanian state news agency Petra.
"The pope's visit to the Holy Land will begin in Jordan," Vatican foreign affairs official Dominique Mamberti said in Amman after meeting Jordan's Foreign Minister Nasser Judeh.
Israel and the Holy See first established diplomatic relations in 1993.