In 1946, when Democratic incumbent James M. Mead decided to run for Governor of New York, Ives successfully ran for Mead's seat in the United States Senate. He faced former Governor Lehman in the general election, during which he became the first Republican to be endorsed by the New York American Federation of Labor. He defeated Lehman by a margin of 52% to 47%. Ives was the first Republican to represent New York in the Senate since James W. Wadsworth, Jr., who was defeated for reelection in 1926.