The authors examined psychiatric comorbidities associated with alcohol use disorders and tobacco use disorders among heterosexual, bisexual, and gay and lesbian men and women in the United States and whether stress-related factors were predictive of comorbidities.The authors used data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (2012-2013, N=36,309) to examine the co-occurrence of past-year alcohol or tobacco use disorder with past-year anxiety disorders, mood disorders, and posttraumatic stress disorder by sexual identity (heterosexual, bisexual, gay or lesbian) and sex. The authors also examined the association of stress-related factors and social support with the presence of comorbidities.Comorbidities were more prevalent among women and sexual minorities, particularly bisexual women. More than half of bisexual (55%) and gay or lesbian (51%) individuals who met criteria for a past-year alcohol use disorder had a psychiatric comorbidity, while only one-third of heterosexual individuals who met criteria for a past-year alcohol use disorder did. Similar differences were found among those who met criteria for a past-year tobacco use disorder. Among sexual minorities, the frequency of sexual orientation discrimination (adjusted odds ratio range=1.08-1.10), number of stressful life events (adjusted odds ratio range=1.25-1.43), and number of adverse childhood experiences (adjusted odds ratio range=1.04-1.18) were significantly associated with greater odds of comorbidities. Greater social support was significantly inversely associated with tobacco use disorder comorbidities (adjusted odds ratio range=0.96-0.97).This research suggests that integrated substance use and mental health prevention and treatment programs are needed, particularly for individuals who identify as sexual minorities. The increased stressors experienced by sexual minority individuals may be important drivers of these high levels of comorbidities.