Sexually transmitted infections (STIs), STI reinfection, human immunodeficiency virus (HIV) acquisition, and changes in behaviors after an STI were examined in a cohort of men who have sex with men (MSM) in Los Angeles, CA. Data from a longitudinal study of MSM enrolled from 2014 with at least 1 follow-up visit through March 2020 were analyzed (n = 447; 1854 visits). Study visits every 6 months included self-interviews for sexual behaviors, substance use, and specimen collection for chlamydia, gonorrhea, syphilis, and HIV testing. Changes in behaviors were assessed using the McNemar test, and participants not diagnosed with an STI served as controls for a difference-in-difference (DiD) analysis of changes over time. Cumulative incidence of an STI was 55% (248 of 447). At 24 months after STI diagnosis, methamphetamine use declined from 50% to 35% ( P < 0.01), and median number of sex partners declined from 5 (interquartile range, 2–11) to 2 (interquartile range, 1–6; P < 0.01). Among participants at risk for HIV and diagnosed with an STI (n = 102), postexposure prophylaxis use was 35% and HIV seroconversion was 6%. Based on DiD analyses, participants diagnosed with an STI had higher levels of substance and a higher number of sex partners when compared with those with no STIs; however, declines in these behaviors were comparable to participants not diagnosed with an STI ( PDID > 0.05). Despite behavior modifications after an STI diagnosis, STI/HIV incidence was high, suggesting that MSM with STIs occupy sexual networks where reductions in sexual and substance using behaviors do not protect them from ongoing exposure to STIs and HIV.