© 2015 American Psychological Association. Objective: This study evaluated whether sexual orientation-specific differences in substance use behaviors exist among adults entering substance abuse treatment. Method: Admissions records (July 2007-December 2009) were examined for treatment programs in San Francisco, California receiving government funding. Lesbian, gay, and bisexual (LGB) persons (n =1,441) were compared to heterosexual persons (n = 11,770) separately by sex, examining primary problem substance of abuse, route of administration, age of first use, and frequency of use prior to treatment. Results: Regarding bisexual males, the only significant finding of note was greater prevalence of methamphetamine as the primary substance of abuse. When compared to heterosexual men, gay and bisexual men evidenced greater rates of primary problem methamphetamine use (44.5% and 21.8%, respectively, vs. 7.7%, adjusted odds ratios [ORs] 6.43 and 2.94), and there was lower primary heroin use among gay men (9.3% vs. 25.8%, OR 0.35). Among LGB individuals, race and ethnicity did not predict primary problem substance, except that among LGB men and women, a non-White race predicted cocaine use (OR 4.83 and 6.40, respectively), and among lesbian and bisexual women, Hispanic ethnicity predicted lower odds of primary cocaine use (OR 0.24). When compared to heterosexual men, gay men were more likely to smoke their primary problem substance (OR 1.61), first used this substance at an older age (M =23.16 vs. M =18.55, p <.001), and used this substance fewer days prior to treatment (M =8.75 vs. M =11.41, p .001). There were no differences between heterosexual and lesbian or bisexual women. Conclusions: There were unique patterns of substance use for gay and bisexual men entering substance abuse treatment, but women did not evidence differences. Gay men evidenced unique factors that may reflect less severity of use when entering treatment including fewer days of use and a later age of initiation of their primary problem substances. The results underscore the importance of being sensitive to differences between gay, bisexual, and heterosexual males when considering substance use disorders.