Purpose: We examined co-occurrences of multiple health-risk behaviors among adolescents in a 5-year longitudinal design as well as their associations with mental health outcomes. Methods: Latent transition analyses explored subgroups of adolescents (N = 229; 51% males) who engaged in distinct patterns of health-risk behaviors and transitions over time. Moreover, longitudinal relations between risk behavior profiles and depressive symptoms were also explored. Results: We identified four latent profiles based on risk levels of safety and violence, sexual behavior, alcohol use, and marijuana and other drug use at both 18 years and 23 years: low risk, modest risk, medium risk, and high risk. Some adolescents maintained their latent profile membership over time, but more transitioned between risk profiles. Adolescents with more depressive symptoms had a higher probability of developing into the high-risk versus low-risk and modest risk profiles at 23 years. Adolescents in the high-risk, low-risk, and modest risk profiles at 18 years developed more depressive symptoms in young adulthood compared with medium risk adolescents. Conclusions: This study provides a better understanding of the prevalence, distribution, and change patterns of health-risk profiles across adolescence and young adulthood in a European American sample. Reciprocal relations between high-risk profiles and depressive symptoms suggest the need for integrated but tailored prevention and intervention programs. Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine.