Billionaire Winfrey, one of the most influential women in the US, has hosted the show since 1986.
A spokesman for the star's Harpo production company would not say why she had made the decision, but said she would discuss it on Friday's show.
Winfrey is expected to focus instead on the launch of her own TV channel.
The Oprah Winfrey Show is a media institution in the US, with an average of seven million viewers.
The BBC's Richard Lister in Washington says the show's open atmosphere and frank conversation redefined the talk show genre and made Winfrey the wealthiest black woman in the world.
Authors appearing on the show often become bestsellers overnight and Winfrey's support for US President Barack Obama was seen as crucial to his presidential election campaign.
Oprah is still the highest-rated talk show on US television but audiences are half what they were a decade ago.
Her empire also includes magazines, a radio show and from next year, a television network, so it would seem likely her place in American culture will continue.
OWN, the Oprah Winfrey Network, is scheduled for launch in 2011.
Via bbc
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