The objectives of this study were to characterize men who have sex with men (MSM) with intention to serosort and to identify factors associated with subsequent failure, defined as potentially discordant unprotected anal intercourse (PDUAI) events. Time-location sampling was used to recruit MSM into a longitudinal study of seroadaptive behaviors in San Francisco. Intention to serosort was assessed at baseline, while sexual behavior in the subsequent 6 months was assessed at follow-up. HIV-negative frequent methamphetamine users were less likely (odds ratio [OR] = 0.14; 95% CI [0.03, 0.81]) and HIV-positive frequent methamphetamine users were more likely (OR = 1.99; 95% CI [1.07, 3.69]) to intend to serosort than nonusers. Among HIV-positive and HIV-negative MSM with intent to serosort, those who frequently used alcohol, methamphetamine, or "downers" had significantly more episodes of PDUAI compared to nonusers. Challenges to serosorting, particularly substance use, should be addressed in HIV prevention and treatment programs that promote seroadaptive behaviors.