The "Full House" and "ER" star took the stand during the federal trial of Allison Coss and Scott Sippola, who are accused of demanding money from Stamos, saying they had photos of him with cocaine and strippers they could sell to a magazine.
Under questioning by prosecutors, Stamos said he met Coss in Orlando, Florida, in 2004 after he was taken there by friends trying to cheer him up after separating from his wife, actress and supermodel Rebecca Romijn.
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"I was very heartbroken at the time," he said.
Stamos said he met Coss at Pleasure Island, a club where patrons must be at least 18. The 46-year-old Stamos said Coss told him she was on "college" spring break.
Stamos said Coss and a friend were among several people who came to his hotel room and stayed for a couple hours. He described their time together as "just hanging out" and "socializing."
He said he later began communicating with Coss via e-mail and described their conversations and "flirty" but "friendly."
"It was all very sweet. I considered her a friend," Stamos said.
Defense attorney Sarah Henderson had alleged that Coss met Stamos when she was 17 and that the two had a romantic fling, which his attorney denies.
Henderson said during opening statements on Monday that two women who worked as strippers eventually showed up in Stamos' hotel room with a bag of cocaine, and Coss and her friend took a picture of Stamos bending over a table where the drugs had been laid out.
Henderson said Stamos and Coss later kissed on a bed and got into a hot tub together after Stamos undressed and Coss stripped to her underwear. She said Stamos offered to perform oral sex on Coss, but she declined. Florida law makes it a second-degree felony for someone 24 or older to have oral sex with anyone 16 or 17 years old.
Stamos eventually became frustrated, broke a bedpost with his hand and left the room before apologizing and inviting Coss to spend the night, which she did, Henderson said.
Stamos declined to comment to The Associated Press after Monday's opening statements. But his attorney, William Sobel, issued a statement through publicist Matt Polk denying the defense's claims.
Stamos received two e-mails last fall from a "Jessica T" who claimed she was pregnant and Stamos was the father, Assistant U.S. Attorney Maarten Vermaat said. Later came a series of e-mails from a "Brian L" describing allegedly compromising photos and saying they would be sold to tabloids if Stamos did not buy them for $680,000.
Prosecutors contend Coss and Sippola sent the e-mails.
Henderson acknowledged Coss was "Jessica T" but described the e-mails as a ruse to test Stamos' reaction in hopes of determining whether he was preying on young girls.
Stamos contacted the FBI, Vermaat said. Two agents testified about a sting operation that ended with Coss and Sippola's arrest at K.I. Sawyer International Airport near Marquette, where an agent posing as a Stamos representative had promised to leave a bag of cash.
"This is really just a get-rich-quick scheme that is based on lies and betrayal," Vermaat told the jury of eight men and four women.
Defense attorneys said their clients had a right to try to sell photos to Stamos and considered it a legitimate business transaction, not a crime.