Oxidative stress is well documented in HIV infection, but the effect of concomitant substance abuse is largely unknown. We studied oxidative stress in our macaque model of morphine abuse and AIDS. In plasma, we found an approximately 50% decrease in catalase activity with morphine dependence that was exacerbated by infection in rapid progressors. Superoxide dismutase was decreased by a similar degree, but only in the presence of both morphine and viral infection. The loss of these antioxidant systems was coincident with significantly increased plasma malondialdehyde upon viral infection that displayed a synergistic increase in conjunction with morphine and rapid disease.