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As an opera company director

Domingo began an affiliation with the Washington National Opera in 1986, when he appeared in its world premiere production of Menotti's Goya. This was followed by performances in a production of Tosca in the 1988/89 season. Beginning in the 1996/97 season, he took on the role of Artistic Director, bringing new life to the company's productions through his many connections to singers throughout the world and his own annual appearances in one role each season. One example of his ability to bring new singers to the stage were those by the then up-and-coming Anna Netrebko as Gilda in Rigoletto during the 1999/2000 season. In 2003 Domingo became General Director and his contract was extended through the 2010–2011 season.

Parallel to Domingo's management of the Washington company, he had been Artistic Director of the Los Angeles Opera since 2000. He assumed the position of General Director of the company in 2003. On 20 September 2010, he announced that he would renew his contract as General Director through 2013. A week later he announced that he would not renew his contract as General Director of the Washington National Opera beyond its June 2011 expiration date. Reaction to this included The Washington Post ' s comments on his accomplishments:

Domingo attempted to quash criticism in East Coast newspapers that he was taking on too much when the singer gave an interview in the Los Angeles Times in which he restated his long-time motto, "When I rest, I rust".

In October 2019, Domingo resigned as general director of the Los Angeles Opera amid accusations of sexual harassment.