There is a substantial body of literature that demonstrates that substance use and lower educational attainment are associated with poorer antiretroviral (ART) adherence, however, the nature of these relationships are not well understood. The purpose of this study was to explore whether coping styles mediate the relationship between substance use and educational attainment and ART adherence in order to better understand how these variables relate to adherence. The sample consisted of 192 HIV-positive patients (mean age = 41 years; 75.5 % male, 46.9 % heterosexual; 52.6 % with a high school/GED education or less) who were on ART. Path analysis revealed that active and avoidant coping significantly mediated the relationship between drug use and ART adherence. No form of coping was found to mediate the relationship between either binge drinking or educational attainment and adherence. Findings suggest that a focus on coping skills should be included in any multimodal intervention to increase ART adherence among HIV-positive drug using patients.