This study examined baseline gender differences among HIV-positive methadone maintenance outpatients currently prescribed antiretroviral medications. Participants were enrolled in a larger clinical trial, which included a 4-week observation period using electronic monitors to track medication adherence. Contrary to previous literature, no significant differences were detected between men (n = 42) and women (n = 36) on medication adherence or depression. Both groups showed remarkably poor adherence during baseline (M = 56% of doses taken on time), high overall prevalence of depression (47%) and illicit cocaine use (47%). Women reported significantly more medication side effects (M = 21.4 vs. 14.9), higher severity of ASI psychiatric problems (M = 0.50 vs. 0.40), and lower SF-36 health-related quality of life in physical (M = 42.1 vs. 63.3) and emotional functioning (M = 26.9 vs. 58.9) than men. Women tested positive for opioids at higher rates than men (53% vs. 29%, respectively), whereas men were more likely to be positive for benzodiazepines than women (26% vs. 6%, respectively). Findings suggest that gender differences between male and female methadone maintenance patients have relevance to treatment providers. Extensive assessment, specialized medical care and mental health services may be warranted in the treatment of HIV-positive female drug abusers.