Objective: Examine the association of health risk behavior clusters with mental health status among US college students. Participants: 105,781 US college students who completed the Spring 2011 National College Health Assessment. Methods: We utilized the latent class analysis to determine clustering of health risk behaviors (alcohol binge drinking, cigarette/marijuana use, insufficient physical activity, and fruit/vegetable consumption), and chi-square and ANOVA analyses to examine associations between the class membership and mental health (mental health diagnoses, psychological symptoms, and self-injurious thoughts/behaviors). Results: Three classes were identified with differing rates of binge drinking, substance use, and insufficient physical activity but similar rates of insufficient fruit/vegetable consumption. Students classified with the highest rates of binge drinking and cigarette/marijuana use had the highest rates across all mental health variables compared to other classes. Conclusions: Students who reported engaging in multiple health risk behaviors, especially high alcohol and cigarette/marijuana use, were also more likely to report poorer mental health.