The persistence of disparities in STI/HIV risk among a new generation of emerging adult gay, bisexual, and other men who have sex with men (YMSM) warrant holistic frameworks and new methodologies for investigating the behaviors related to STI/HIV in this group. In order to better understand the continued existence of these disparities in STI/HIV risk among YMSM, the present study evaluated the presence and persistence of syndemic conditions among YMSM by examining the co-occurrence of alcohol and drug use, unprotected sexual behavior, and mental health burden over time. Four waves of data, collected over the first 18 months of a 7 wave, 36-month prospective cohort study of YMSM (n = 600) were used to examine the extent to which measurement models of drug use, unprotected sexual behavior, and mental health burden remained consistent across time using latent class modeling. Health challenges persisted across time as these YMSM emerged into young adulthood and the measurement models for the latent constructs of drug use and unprotected sexual behavior were essentially consistent across time whereas models for mental health burden varied over time. In addition to confirming the the robustness of our measurement models which capture a more holistic understandings of the health conditions of drug use, unprotected sex, and mental health burden, these findings underscore the ongoing health challenges YMSM face as they mature into young adulthood. These ongoing health challenges, which have been understood as forming a syndemic, persist over time, and add further evidence to support ongoing and vigilant comprehensive health programming for sexual minority men that move beyond a sole focus on HIV.