Santos had traveled to Havana to discuss a controversy over Cuba's participation with Raúl Castro and Venezuelan President Hugo Chávez, who is in Havana convalescing from surgery to remove a cancerous tumor.
Members of the leftist Bolivarian Alliance, or ALBA, demanded last month that Cuba be included in the April 14-15 Summit of the Americas in Cartagena, Colombia, but stopped short of threatening a boycott while urging Santos' government to extend an invitation.
As host, Colombia gets the final decision.
"As we have said from the beginning, (the summit) is a matter that requires consensus, a consensus that unfortunately we have not been able to find," Santos said at Havana's international airport Wednesday night prior to departing.
"We made it clear to President Castro that although we truly appreciate his desire to be part of this gathering, under such circumstances without having reached consensus it is very difficult to extend an invitation to him."
Santos thanked Castro for his expressing a desire not to create problems for the summit or for Colombia, and also said he respects other nations' wish for Cuba to take part in regional gatherings.
"Colombia hopes that the situation of Cuba, its participation, be discussed in a constructive manner and respectfully at the Cartagena summit. ... It is a matter that has been many years without a solution.
Colombian Foreign Minister María Angela Holguín told reporters that during Santos' visit with Chávez, the Venezuelan leader indicated that, health permitting, he will go to the summit and Nicaragua has also confirmed its attendance. Both nations are members of ALBA.
"We hope that everyone comes," Holguín said.
Washington, a staunch supporter of Santos, opposes Cuban inclusion in the Summit of the Americas. Santos has sought to maintain friendly ties to Cuba, and his efforts to remain on good terms with Chávez have dramatically set him apart from his predecessor.
The Summit of the Americas is historically linked to the Organization of American States, and Cuba has not participated in the OAS since 1962. But Cuba has expressed a desire to attend the Cartagena summit.
U.S. officials say Cuba, ruled since 1959 by brothers Fidel and Raál Castro, does not meet OAS standards of democracy and thus has no business taking part.
"They don't fit the definition of democratic countries and the development of democracy in the hemisphere," U.S. Secretary of State Hillary Clinton said last week at a hearing of the House Foreign Affairs Committee. "So at this point we see absolutely no basis and no intention to invite them to the summit."
Geoff Thale, an analyst at the Washington Office on Latin America, a U.S.-based think tank, said the fact that Santos was going out of his way to smooth over the flap, together with ALBA's support for Cuba, shows that the region is increasingly willing to deviate from U.S. international policy.
"The widespread support in Latin America for Cuba's participation in the Summit, and the willingness of many governments to push the issue, underscores the decline of U.S. influence in the region," Thale said by e-mail.
In Havana, Santos and Chávez gave a green light to bilateral accords that they were to have discussed on March 1 before Chávez's illness interrupted plans to get together.
"We found (Chávez) in good health considering the circumstances he has had to go through. We found him happy, in good spirits, walking around the side of the hospital," Santos said.
"He told me he would stay a few days more (in Cuba) and planned to return to Venezuela early next week."
ALBA, Chávez's brainchild, is made up of Antigua and Barbuda, Bolivia, Cuba, Dominica, Ecuador, Nicaragua, St. Vincent and the Grenadines and Venezuela.
Based on reporting by the Associated Press.