Methamphetamine (MA) dependence and HIV infection are independently associated with cerebral dysfunction, especially within frontal-basal ganglia circuits. Recent evidence indicates that MA dependence has an additive effect on neuropsychological (NP) deficits associated with HIV infection. This study extends prior findings by examining the combined effects of MA dependence (MA+) and immunosuppression (i.e., CD4 lymphocyte count <200) on NP functioning in 284 HIV+ individuals. Prevalence of NP impairment was examined in four demographically comparable groups: (1) MA+/CD4 < 200; (2) MA+/CD4 > or = 200; (3) MA-/CD4 < 200; and (4) MA-/CD4 > or = 200. Results revealed that both MA dependence and immunosuppression were significant predictors of NP impairment. More importantly, additive effects were evident whereby the MA+/CD4 < 200 group exhibited the highest rate of NP impairment. Findings indicate that MA dependence conveys an additive deleterious impact on NP status in immunosuppressed persons with HIV infection, perhaps reflecting the combined effects of neuropathophysiological mechanisms in fronto-striatal circuits.