"I wish to renew the Christian message for cooperation and peace among all peoples, especially among those that surround this sea - an ancient cradle of civilization - and those in the Near and Middle East," he told the faithful gathered in a large industrial space by the city's ferry port.
Quoting from his own speech to the United Nations in April, Benedict said conflict resolution should be sought "by exploring any possible diplomatic way, by paying attention and giving encouragement to the weakest signs of dialogue and desire for reconciliation."
The crowd - an estimated 70,000 people - cheered as Benedict arrived in his popemobile waving and smiling. The pope celebrated an open-air Mass and delivered the Sunday Angelus prayer.
Among those attending was the Gennadios, the Greek Orthodox metropolitan of Italy and exarch of Southern Europe. The pope said he was "especially happy" about the Greek Orthodox presence and called for prayers and work to reach Christian unity, reaffirming a main goal of his papacy.
The pope's remarks Sunday touched on a variety of themes.
He called for Mary's help in shielding Italy, Europe and the whole world from "the storms that threaten faith and true values." He explained that Christian compassion must not be mistaken with giving handouts.
Finally, he had a message for Christian sinners, telling them that nobody was born a saint and describing the Roman Catholic Church as a "community of sinners who believe in the love of God."
"The 12 Apostles were not perfect men who were chosen for their moral and religious flawlessness," he said. "They had human limits, sometimes even grave ones."
The pontiff is on a two-day trip to the Puglia region, which makes up Italy's "heel." On Saturday, he traveled to the southernmost tip. He was to meet with local clergy later Sunday before returning to the Vatican.