Neuropsychological (NP) impairment is multiply determined among HIV-infected and HIV-uninfected individuals who are also dually diagnosed with depression and who use illicit substances. The purpose of the present study was to assess the impact of HIV status, depression, and problematic substance use on NP performance. A total of 160 opiate-dependent outpatients undergoing methadone maintenance (80 HIV-infected, 80 HIV-uninfected) completed diagnostic and NP evaluations. Raw scores from individual NP tests were converted to Z scores relative to standard norms and were averaged to form a composite score. HIV-infected participants had significantly lower overall NP performance--as well as lower performance on tests of attention, motor speed, and verbal memory--than HIV-uninfected participants. In multiple regression analyses considering the role of depression and substance use, only HIV status emerged as a significant predictor of NP impairment. These findings confirm NP impairment in HIV-infected substance abusing patients independent of comorbid depression and severity of substance use.