Syphilis is a sexually transmitted disease (STD) caused by infection with the spirochete Treponema pallidum, and like other genital ulcer diseases, syphilis enhances the transmission of human immunodeficiency virus (HIV). During the 1990s, syphilis occurred predominantly among heterosexual blacks in the South and in large cities. However, recent outbreaks of syphilis have occurred among men who have sex with men (MSM). A large syphilis outbreak occurred among MSM during January-July 2000 in southern California. During the outbreak period, the proportion of primary and secondary (P&S) syphilis cases among MSM increased to 51% from 26% for the same period in 1999. This report summarizes the findings of an investigation of this syphilis outbreak, which indicate a substantial increase in the number of syphilis cases among MSM, many of whom are HIV-positive. These data suggest that concern about HIV infection may be declining among MSM and emphasize the importance of strengthening efforts to prevent HIV infection in this population in the United States.