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After weeks of scarce public appearances, Chavez, 58, announced in a letter on Tuesday that he was going to Havana for therapy known as "hyperbaric oxygenation" - a method used to reduce bone decay caused by radiation therapy.
In Cuba, Chavez enjoys the friendship of past and present Cuban leaders Fidel and Raul Castro, plus guaranteed privacy on the tightly controlled Caribbean island.
Venezuelans, who have been endlessly speculating about Chavez's cancer since it was diagnosed in mid-2011, were not sure what to make of the latest twist - debating whether it was normal post-radiation treatment or a serious downturn.
"I really don't know what he has," Chavez's cousin, Guillermo Frias, told Reuters from the president's rural hometown state Barinas. "But anyway, I always pray for him every night. I stop at a shrine on the corner and always remember him.
"I hope he recovers fine. I'm sure he will. The election campaign was tough for him. He went too far."
Though he had declared himself cured, Chavez appeared exhausted at the end of his successful presidential re-election bid in October. He later admitted radiation had taken its toll.
The normally garrulous and omnipresent leader has made only a few, relatively short public appearances, mainly on state TV, at his presidential palace since his victory on October 7.
One opposition newspaper dubbed him "The Invisible Man".
Unlike multiple past trips to Cuba, during treatment for three operations on two tumors in his pelvic area, state TV did not show images of Chavez departing or arriving this time.
Chavez has open-ended authorization from Congress to travel, but aims to be back at least for the Jan. 10 start of his new term, if not for a couple of regional summits before.
His absence leaves newly appointed Vice President Nicolas Maduro, 49 - a former bus driver and union leader - in a prominent position amid speculation among Venezuelans over who could replace Chavez should he leave power.
Congress head Diosdado Cabello, a former military comrade of Chavez, is also often touted as a possible successor to lead the ruling Socialist Party. Under the constitution, an election would have to be held if Chavez were to leave office within the first four years of his new six-year term.
Chavez's return to Cuba overshadowed the buildup to state elections in Venezuela on Dec. 16, where the opposition aims to overcome disappointment at their failure to win the presidency.
A prolonged absence by Chavez could potentially postpone major policy decisions, such as a widely expected devaluation of the bolivar currency after heavy pre-election state spending.