ABSTRACT: An estimated one- to two-thirds of incident HIV infections among U.S. men who have sex with men (MSM) occur within the context of a primary relationship. The existing, yet limited, literature on sexual risk behavior among same-sex couples suggests that MSM with main partners are more often to report having lower perceived HIV risk, higher unrecognized HIV infection, and increased frequency of condomless anal intercourse with their primary partner. Furthermore, numerous studies document the strong relationship between polydrug use and binge drinking with HIV infection among MSM. However, more research is needed that identifies how individual- and relationship-level factors are related to polydrug use and binge drinking in the context of same-sex male relationships. We used baseline data collected as part of a prospective randomized controlled trial of 160 same-sex male couples (total N?=?320 individuals). In 2015, recruitment commenced in three U.S. cities: Atlanta, GA, Boston, MA, and Chicago, IL. Participants completed a self-report assessment using an audio-computer-assisted self-interview system during their baseline enrollment visit. We collected information on participants' sociodemographic characteristics, drug and alcohol use, individual- and relationship-level variables of interest, as well as relationship quality. Multinomial logistic regression models were fit for three different categories of polydrug use and of binge drinking for which (1) both partners exhibited the behavior, (2) only the respondent exhibited the behavior, or (3) only the partner exhibited the behavior. Participants' age ranged from 18 to 69 (M?=?35.9). The sample majority (77.5%) was White (248/320), with 12.2% Black (39/320) and 10.3% Multiracial (33/320); 68.4% had completed a college degree; and 9.6% were unemployed. A high proportion (62.2%) reported any drug use, including marijuana; 45% reported using drugs other than marijuana; and 18.1% reported polydrug use. Overall, 22.2% reported current binge drinking. Age discordance and being in a long-term relationship (6 or more years) were associated with a decreased odds of polydrug use among couples; being in an interracial dyad, recent history of arrest, living with HIV, and self-reported clinically significant depressive symptoms were associated with an increased odds of polydrug use. Additionally, being the older partner and reporting higher levels of internalized homophobia decreased odds for binge drinking, while recent history of arrest, living with HIV, and feeling more loved in their relationship were associated with an increased odds of binge drinking. Findings have implications for developing interventions to reduce substance use and promote health among same-sex male couples. Future research would benefit by using longitudinal study designs to understand the individual-, relationship-, and structural-level factors that potentiate polydrug use and binge drinking among same-sex male couples.