Pope Benedict has prayed for freedom and renewal "for the greater good of all Cubans" and asked for Good Friday to be made a public holiday in communist Cuba.
In a 55-minute closed-door sit-down with President Raul Castro, the Pontiff proposed that Good Friday, when Catholics commemorate the death of Christ, be made a holiday.
The Vatican spokesman, the Rev. Federico Lombardi, said it was natural for the government to take time to consider the request, which echoed a successful appeal by John Paul II in 1998 for Cuba to make Christmas a holiday.
"It's not that it changes reality in a revolutionary way, but it can be a sign of a positive step - as was the case of Christmas after John Paul's visit," the Rev. Lombardi said.
Asked if the Pope raised the matter of political prisoners or Alan Gross, a US government subcontractor sentenced to 15 years jail in Cuba on spy charges, the Rev. Lombardi said "requests of a humanitarian nature" came up, but he had no information about whether individual cases were discussed.
Days after dismissing the Marxist ideology on which the Cuban system is based, Pope Benedict continued to gently press themes highly sensitive to Cuban Government in his prayer and short speech at the sanctuary of the Virgin of Charity of Cobre near the eastern city of Santiago.
"I have entrusted to the Mother of God the future of your country, advancing along the ways of renewal and hope, for the greater good of all Cubans," the Pope said. "I have also prayed to the Virgin for the needs of those who suffer, of those who are deprived of freedom, those who are separated from their loved ones or who are undergoing times of difficulty."
It wasn't long before a top official back in Havana responded.
"In Cuba, there will not be political reform," said Marino Murillo, Cuba's economic czar and a vice president.
The Pope has kept his language lofty, his criticism vague and open to interpretation, but Murillo's comments left no room for doubt, and they were quickly picked up by pro-government blogs and on Twitter accounts.
Mr Castro has said that opening up Cuba's political system would inevitably spell doom for its socialist project since any alternative party would be dominated by enemies across the Florida Straits and beyond.
Alfredo Mesa, a Cuban-American National Foundation board member whose trip to Cuba was organised by the Miami Archdiocese, said the Government's strong reaction would reinforce the Pope's message and the need for change.
"I'd rather have them say this now than tomorrow," Mr Mesa said.
During a quiet moment at the shrine of the Virgin of Charity, Pope Benedict also prayed for more Cubans to embrace the faith in a country that is the least Catholic in Latin America. While most Cubans are nominally Catholic, fewer than 10 per cent practice the faith.
In subtle ways, the Pope has acknowledged a lack of faith in the island nation, and tried to make his trip appealing to potential believers. The visit is timed to the 400th anniversary of the appearance of the statue of the Virgin to two fishermen and an African slave in Cuba's Bay of Hipe.
Dunia Felipillo, 45, said she was proud to see the pope praying before the Virgin of Charity, even though she herself was not Catholic.
"We all ask favours of la Cachita," she said, using the Cuban slang for the Virgin, as she watched the ceremony on TV from the lobby of a Santiago hotel.
Meanwhile, dissidents on the island say they still don't know the man who yelled "Down with the Revolution! Down with the dictatorship!" before the Ppe's Mass on Monday in Santiago.
Security agents hustled him away. Video of the incident showed him being slapped by another man wearing the uniform of a first-aid worker before security agents separated them.
Miami Archbishop Thomas Wenski, who led a pilgrimage of about 300 mostly Cuban-Americans to the island for Benedict's visit, got a sustained standing ovation on Tuesday when he gave a homily in a Havana cathedral packed mostly with Floridians.
Archbishop Wenski called for increased respect for human rights and political change on the island, while also warning against unbridled capitalism.