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The Desert Inn’s most famous guest, the billionaire Howard Hughes, arrived on Thanksgiving Day in 1966, renting the hotel's entire top floor. After staying past his initial ten-day reservation, he was asked to leave in December 1966 so that the resort could accommodate the high rollers who had been promised those suites. Instead of leaving, Hughes decided to start negotiations to buy the Desert Inn, and on March 1, 1967, he purchased the resort for around $13 million. This purchase was the first of many Vegas resort purchases by Hughes.

On April 27, 2000, the resort was purchased by Steve Wynn, who closed it several months later. On October 23, 2001, the main tower was demolished to make room for a megaresort that Wynn planned to build. Originally intended to be named "Le Reve", the Wynn Las Vegas opened on April 28, 2005, his wife’s birthday.

The Desert Inn saw its last use as the Las Vegas set for Rush Hour 2 and was converted to resemble an asian themed casino. The old towers were then used as a small museum to display some of Wynn's art collection and as offices for Wynn Resorts. The last remaning tower has been removed.

The Desert Inn was the last Strip hotel with its own golf course.