The former Beatles singer made his return in Albany, New York, leading his band in a version of the Fab Four's Eight Days a Week.
He made no immediate reference to the virus that briefly hospitalised him in Japan.
The 72-year-old cancelled a tour of Japan and concerts in South Korea and the US.
He last played in Costa Rica on May 1.
He wore black trousers and a sky blue blazer. When he took the jacket off four songs in, he joked it would be the evening's only wardrobe change.
Sir Paul paid tribute to former songwriting partner John Lennon with the song Here Today, which he described as the conversation they never had.
He also honoured another late rock star, Jimi Hendrix, with an instrumental interlude of Purple Haze.
Sir Paul's wife, Nancy, was on hand for the return. He dedicated his song My Valentine to her.
It has been a busy year for Sir Paul, who marked the 50th anniversary of his first appearance on The Ed Sullivan Show this winter. He has 19 US shows scheduled, including one at Candlestick Park in San Francisco, where the Beatles made their final concert appearance in 1966.
The other surviving ex-Beatle, Ringo Starr, is also on the road this summer.