Nathan was promoted to the San Francisco Giants on April 20, 1999, taking the roster spot of superstar slugger Barry Bonds, who went on the disabled list after left elbow surgery. He made his major league debut the next day, pitching seven shutout innings and winning his first major league decision against the Florida Marlins, 4–0. He then divided the rest of the season between the AAA Fresno Grizzlies and the Giants, going 6–4 with the Griz and 7–4 and 4.18 with the Giants, earning his first career save on May 16 against the Houston Astros.