Polysubstance use has been posited to be a significant contributor to excess burden of HIV disease among men who have sex with men (MSM). The current study investigated polysubstance use and sexual risk among men who utilize Massachusetts Department of Public Health (MDPH) van services (such as HIV, chlamydia, gonorrhea, or syphilis testing; Hepatitis A and B vaccinations) at venues targeting MSM. Participants (n = 214) completed a one-time, cross-sectional survey via an audio computer-assisted self-interview (ACASI) in English or Spanish between June 2007 and September 2007. Fifteen percent of the overall sample did not know their HIV status; 11% reported polysubstance use (concurrent use of three or more: poppers, ecstasy, GHB, cocaine, crystal methamphetamine, Viagra) during sex in the 12 months prior to study enrollment. Polysubstance users were more likely to be HIV infected (odds ratio [OR] = 4.62; p = 0.03) and to have a history of one or more sexually transmitted diseases (STDs; OR = 4.74; p = 0.03) relative to participants who did not report polysubstance use during sex. After controlling for covariates of age, race/ethnicity, education level, insurance status, sexual orientation, STD history, HIV status, and depression, multivariable logistic regression analyses revealed that polysubstance users were 9 times more likely to have reported unprotected anal (insertive or receptive) sex in the 12 months prior to study enrollment (adjusted OR = 9.53; p = 0.007) compared to nonpolysubstance-using MSM. Polysubstance users lacked access to care (21% were uninsured) and the overwhelming majority (96%) were first time users of mobile health van services. Accessible outreach services for MSM such as mobile van services need to include drug screening and interventions that triage men into treatment programs; year-round availability of van services is warranted.