The current study was designed to develop a better understanding of the nature of the relationships between mental health burden, drug use, and unprotected sexual behavior within a sample of emerging adult gay and bisexual men, ages 18-19 (N = 598) and to test a theory of syndemics using structural equation modeling. Participants were actively recruited from community-based settings and the Internet for participation in a seven-wave cohort study. Data for participant characteristics and mental health were collected via computer-assisted survey, while drug use and unprotected sex behaviors for the month prior to assessment were collected via a calendar-based technique. Using the baseline data, we developed and tested structural equation models for mental health burden, drug use, and unprotected sex and also tested a second-order model for a single syndemic. First-order measurement models for each of the three epidemics were successfully identified using observed data. Tests of a second-order model seeking to explain the three epidemics as a single syndemic fit poorly. However, a second-order construct comprised of mental health burden and drug use fit the data well and was highly associated with the first-order construct of unprotected sex. The findings advance a theory of syndemics and suggest that in order to be maximally effective both HIV prevention and HIV care must be delivered holistically such that sexual risk behaviors are addressed in relation to, and in sync with, the drug use and mental health of the individual.