Some studies point out that depression affects the performance of HIV patients in neuropsychological tasks, but at present this effect is not clear. The purpose of the present paper was to study whether the presence of symptoms of depression affects the neuropsychologic performance of seropositive drug users in tasks of attention/concentration, learning and memory, language, construction and visuospatial function, speed of motor performance, cognitive flexibility, manual skill and concept formation and reasoning. In order to carry out this research a sample consisting of 127 male volunteer subjects was used. These subjects were distributed in four groups: one group consisted of HIV-seropositive drug users with symptoms of depression (n = 33); the second group consisted of HIV-seropositive drug users without symptoms of depression (n = 47); the third group was formed by HIV-seronegative drug users with symptoms of depression (n = 15) and the fourth group was formed by HIV-seronegative drug users without symptoms of depression (n = 32). The results reveal the effect of symptoms of depression (evaluated by the Beck Depression Inventory) on the neuropsychologic performance of seropositive drug users. This effect, however, was not observed in the seronegative group. These findings lead us to suggest that symptoms of depression constitute a risk factor for presenting neuropsychologic disturbances in seropositive subjects, which could well be acting as a factor that foments the neuropsychological effects of HIV.