Violence broke out after news of an inspection to confiscate weapons at the Centro Occidental jail, Prisons Minister Iris Varela said in a statement, without providing a death toll.
Local media reports say between 26 and 54 people were killed and dozens wounded.
A prisons ministry source told Reuters that "many" had been killed, including one national guard officer, but declined to offer more details. The source said the ministry would hold a news conference on Saturday with details.
The violence involved both a struggle between rival gangs for control of the jail and a confrontation between inmates and troops called in to calm the situation, Varela said.
Venezuelan prisons are controlled by armed gangs that have rioted repeatedly over the last several years due to disputes with jail authorities or prison leaders.
"Who is going to be blamed for this new massacre in one of our country's jails? Incompetent and irresponsible government," tweeted opposition leader Henrique Capriles.
The South American nation's 34 prisons were designed to hold around a third of the 50 000 inmates now in them, according to local prison advocacy groups. Many of the prisoners are armed and hundreds are killed each year in riots and gang fights.
A month-long siege occurred in 2011 at El Rodeo prison, just outside the capital of Caracas, when 22 died before some 5 000 soldiers restored order. – Reuters