"We have decided to open a criminal investigation into citizen Rafael Ramirez," prosecutor Tarek William Saab said on state television.
Ramirez led PDVSA for a decade before becoming Venezuela's ambassador to the UN, a post from which he resigned last week -- saying it was at Maduro's request.
Ramirez had long been seen as a target of the socialist leader's aggressive push to consolidate power in the run-up to next year's presidential elections in the South American country, wracked by a worsening economic crisis which has seen deadly protests and hyperinflation as well as chronic food and medicine shortages.
Saab said Ramirez's cousin, Diego Salazar -- arrested on December 1 for allegedly diverting and laundering public funds -- "incriminates him as his direct partner" in operations to purchase and sell oil.
Salazar is accused of diverting 1.5 billion euros in public funds to Andorra between 2011 and 2012.
"They seize public resources and illegally seek to legalize the capital," Saab said, referring to people arrested under his anti-corruption drive. He said the figure in Salazar's case could amount to 4.2 billion euros going back to 2006.
Ramirez's whereabouts are unknown since he stood down from his post at the UN.
In interviews granted to some media outlets, from an undisclosed location, he claimed to be a victim of political persecution for his criticism of Maduro's mismanagement of the economy and denied being involved in corruption.
The 54-year-old engineer headed PDVSA between 2004 and 2014, a hugely influential position that stemmed from a close relationship with late president Hugo Chavez.
-- A problem for Maduro --
Isias Medina, a diplomat who worked with Ramirez at the UN, said the former ambassador had long been a target of Maduro but the president had to bide his time because he had been a member of Chavez's inner circle.
Latin America analyst Peter Schechter said Ramirez's effective sacking from his UN post showed that he "was becoming a problem. He needed to be dealt with. Maduro cannot abide by anybody else showing any ability to influence issues in Venezuela."
"He is ruthless about removing any potential adversary," said Schechter, of George Washington University in the US.
Ramirez loyalists have recently been arrested and removed from key posts -- including former oil minister Eulogio Del Pino and ex-PDVSA chief Nelson Martinez -- in what analysts see as an ongoing purge.
They are the highest-ranking officials to be arrested in the anti-corruption moves at PDVSA, which accounts for almost all the country's income.
Speaking to reporters in Caracas, Saab said 67 PDVSA managers had been arrested so far in an anti-corruption drive, 18 of them top managers in the oil giant.
Without specifically mentioning Ramirez, Maduro said last week that "anyone who becomes corrupt is a traitor."
Oil minister Manuel Quevedo, a former general installed to replace both Del Pino and Martinez, told reporters at a recent OPEC meeting that Venezuela's oil production was being sabotaged as a prelude to a coup.
Venezuela, pummelled by US sanctions and teetering on the brink of a full-blown default on its massive debt, has the world's biggest proven reserves of oil.
But because of endemic corruption and a chronic lack of investment, the OPEC member's oil production is falling sharply.
Annual output is around 1.9 million barrels per day, having slumped more than 23 percent between January 2016 and October this year.
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