At the beginning of the 1999–2000 Serie A season, Di Biagio transferred to Internazionale, and became a regular first team member due to his continued high standard of performance. During the 2001–02 season, he narrowly missed out on winning the Serie A title to Juventus on the final match-day; he received criticism, however, for his despondent performance in a 4–2 defeat to Lazio at the Stadio Olimpico in Rome, on his final league appearance of the season, despite initially scoring a goal during the match. Di Biagio remained at Inter until 2003, and during his four years at the club, he amassed 163 appearances, scoring a total of 18 goals in all competitions.