The two men and two women are charged with trading phony works by major modern German artists, including Max Pechstein, Max Ernst and Heinrich Campendonk.
"We are charging them with organized fraud and forging documents," said senior public prosecutor Günther Feld.
The trial is expected to take at least 40 days, as the prosecution has reportedly called around 170 witnesses, including a number of prominent dealers and experts.
Experts say the forgeries are extremely high quality, as are the documents that authenticated them.
"They produced incredibly well-made paintings, including a complete provenance that took familial background and the historical art context into account," said Henrik Hanscheid, head of Lempertz, a 150-year-old art dealership based in Cologne that was duped into selling some of the fakes.
The trial relates specifically to the sale of 14 forged works, all produced in the past decade, while 33 other potential forgeries are still being investigated.
One of the fake paintings was Heinrich Campendonk's "Red Picture with Horses," which was sold by a number of renowned auction houses and galleries before it was identified as a fake.
One expert, Werner Spies, who knew artist Max Ernst personally, incorrectly identified five of the forgeries as authentic. He is now being sued for damages by a French art dealer.
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The accused include two granddaughters of Werner Jäger, a wealthy businessman who died in 1992, as well as one of their husbands and an associate. Many of the works they forged were presented as coming from Jäger's extensive art collection.