ABSTRACT Aims Several decades of research have shown that lesbian, gay and bisexual (LGB) adults are at high risk for substance use and substance use disorders, and a recent meta-analysis shows that these disparities most probably begin in adolescence; however, no studies to date have examined longitudinal growth in substance use in LGB youth and heterosexual youth to determine if they follow different trajectories into young adulthood. The primary aims of this paper were to estimate individual trajectories of substance use in youth and examine differences between self-identified LGB and heterosexual subsamples. Method A school-based, longitudinal study of health-related behaviors of adolescents and their outcomes in young adulthood was used to test our hypotheses (The National Longitudinal Study of Adolescent Health). Participants were included if they were interviewed at all three waves and were not missing information regarding self-identified sexual orientation (n = 10 670). Results Latent curve models (LCMs) showed that LGB identity was associated significantly with individual variability in substance use intercepts and slopes, above and beyond age, race and gender. Self-identified LGB youth reported higher initial rates of substance use and on average their substance use increased over time more rapidly than did substance use by heterosexual youth. Two other indicators of sexual orientation (same-sex romantic attraction and same-sex sexual behavior) were also associated with substance use trajectories, and differential results were found for youth who identified as ‘mostly heterosexual’ and bisexual compared with youth who identified as completely heterosexual or homosexual. Conclusions Sexual orientation is an important risk marker for growth in adolescent substance use, and the disparity between LGB and heterosexual adolescents increases as they transition into young adulthood. More research is needed in order to examine: causal mechanisms, protective factors, important age-related trends (using a cohort-sequential design), the influence of gay-related developmental milestones, curvilinear effects over time and long-term health outcomes.