Although studies show that adolescents with same-sex parents experience homophobic discrimination, little is known about associations between stigmatization and substance use in this population. The 17-year-old offspring of lesbian parents from the largest, longest-running, longitudinal study of same-sex parented families were surveyed about substance use, experiences of homophobic stigmatization, and overall life satisfaction. Compared to matched adolescents from a national probability sample, adolescents with same-sex parents were more likely to report occasional substance use but not more likely to report heavy use. No associations were found between substance use and homophobic stigmatization or life satisfaction.