This study aimed to examine gender moderation within a stress and coping model of HIV medication adherence in adults with a history of childhood sexual abuse (CSA). Sequelae of CSA, including negative coping, psychological distress, and drug use, interfere with adherence to highly active antiretroviral treatment (HAART). These obstacles to adherence are likely moderated by gender. Gender may particularly influence the mediational effect of drug use on adherence. Participants included 206 adults living with HIV/AIDS and CSA. Categorical/continuous variable methodology in a structural equation modeling framework was used to test a multigroup model with women and men. Gender significantly moderated several effects in the model. For women, the effect of psychological distress on HAART adherence was mediated by drug use and the effect of drug use on viral load was mediated by HAART adherence. Among men, drug use did not significantly impact adherence. Since gender appears to moderate the effect of drug use on medication adherence, it is particularly important to address drug use within the context of HIV disease management in women with a history of CSA. Further, interventions to increase HAART adherence should take trauma history, gender, and drug abuse into account when assessing efficacy.