Prinze worked at several comedy clubs in New York City, including Catch a Rising Star and The Improv. For his budding career as a comedian, he changed his name to Prinze. He chose that because, according to his friend David Brenner, he wanted to be known as the "King" of comedy, but Alan King already had that last name, so he would be the "Prince" of comedy instead.

In 1973, he made his first TV appearance on one of the last episodes of The Jack Paar Show. In December 1973, he had his biggest break, an appearance on The Tonight Show Starring Johnny Carson. Prinze was the first young comedian to be asked to sit down and chat with Carson on his first appearance. He went on to appear, as well as guest host, The Tonight Show on numerous occasions after that.

From 1974 to 1977, he starred as Francisco "Chico" Rodriguez in the NBC TV series Chico and the Man with Jack Albertson. Both Prinze and the show were an instant hit.

Prinze made several appearances on the Dean Martin Celebrity Roasts, most notably at the roasts for Sammy Davis Jr. and Muhammad Ali.

In 1976, he starred in a made-for-TV movie, The Million Dollar Rip-Off. Also in 1975, he released a comedy album that was taped live at Mr. Kelly's in Chicago titled Loooking Goood, his catch phrase from Chico and the Man.

Prinze had a little-known talent for singing, examples of which were heard in the background of the title song of the Tony Orlando and Dawn album To Be With You, in his appearances on their variety show, and on rare occasions on his own sitcom.

Prinze dated actresses Lisa Farringer, and Pam Grier, among others. He was also good friends with Kitty Bruce, daughter of the late Lenny Bruce, whom Prinze admired. He and Kitty Bruce were reported to have been engaged to be married at one time, but the rumor was never substantiated.

He married Katherine Cochran in October 1975. They had one son, Freddie James Prinze, who later became an actor. The son's middle name was in honor of James Komack, producer of Chico and the Man.

In 1976, after his arrest for driving under the influence of Quaaludes, his wife filed for divorce on the grounds that his escalating dependence on drugs was endangering her and their son.

In 2001, TV Land began showing reruns of Chico and the Man. The show became popular once more and gained a whole new generation of fans for Prinze and the show, as well as rekindling the interest of old fans.

In 2005, Freddie Prinze Jr. had a show on ABC called Freddie. Although it didn't last long, it was notable for two things: The pilot episode was dedicated to Freddie Prinze. Prinze Junior's production company is called Hunga Rican, Excitable Boy, and in the background, Prinze Senior is heard saying: "Looking Good!"

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