"I hope he has the opportunity to meet Karl Marx very soon
" McCain told a town-hall style meeting of about 150 people, referring to communist theoretician Marx who died on March 14, 1883.
Castro, 81, announced on Tuesday he was stepping down as president and commander-in-chief of Cuba's armed forces after 49 years in power. His brother Raul Castro is expected to be named Cuba's new head of state on Sunday.
"Apparently he is trying to groom his brother Raul," McCain said. "Raul is worse in many respects than Fidel was."
Castro has not appeared in public since undergoing stomach surgery and handing power temporarily to Raul in July 2006.
McCain, a four-term Arizona senator, has an almost insurmountable lead over his last major Republican rival, former Arkansas Gov. Mike Huckabee.
McCain's approach to Cuba has generally echoed that of US President George W Bush, who has tightened a decades-long trade embargo and has rejected easing sanctions without a transition to democracy.
McCain, who is popular among conservative Cuban-Americans, also has said that if he wins the November 4 US presidential election he would keep up pressure for political change in Cuba's one-party state.
That includes a travel ban and trade and financial sanctions enforced a few years after Castro's 1959 revolution on the Caribbean island.
McCain, 71, a former prisoner of war in Vietnam, has accused Cubans of participating in the torture of some of his fellow prisoners in Hanoi during the Vietnam War.