His favourite target is his employer, CBS, or, more precisely, the industrial giant that bought the network last year, Westinghouse. Its kitchen appliances are fodder for regular ridicule.
But Mr Letterman, whose ratings have been sliding since his widely panned appearance as host of last year's Oscars ceremony, may be about to get some just deserts from one victim who did not find his ribbing in the least bit amusing. The "Peach Lady" is hitting back.
Jane Bronstein became a regular feature on Late Night with Letterman last September, when CBS cameras caught her among spectators at the US Open tennis in New York attempting to eat a peach. It was an especially juicy one and Ms Bronstein was unable to stop the juice streaming down her chin.
In what became a running gag for Mr Letterman, he showed footage of Ms Bronstein and the peach at least half a dozen times during September. He launched a tongue-in-cheek national competition to discover the peach- eater's identity and had her image broadcast from the giant-sized TV screen in Times Square, New York.
Where Mr Letterman may have stepped over the line was in calling Ms Bronstein a "seductive temptress". In fact, she is a large woman with a thyroid condition who suffered polio as a child and has had two spinal fusions.
So Ms Bronstein, 54, is suing the TV star for ridiculing her. A lawsuit filed in Stamford, Connecticut, where Ms Bronstein lives and which is also close to the suburban home of Mr Letterman, accuses the performer and Worldwide Pants, the company that produces his nightly show, of invading her privacy. The amount of damages being sought has not been disclosed.
Mr Letterman has suddenly gone mum on the subject of the Peach Lady and his publicist in New York, from where his show is broadcast, is also refusing to comment. Worldwide Pants, however, has expressed surprise at the court action. "The company's attorneys believe the suit is completely unwarranted," it said in a statement.