Abstract In view of the rising prevalence of an overweight body mass among patients living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), clinicians must now be mindful of possible adverse outcomes resulting from the co-occurrence. The present study was designed to examine the additive and interactive effects of HIV/AIDS and an excess body mass, as well as the additional contributions of substance abuse or dependence. The dependent variable was brain function estimated by the measurement of P300 electroencephalographic potentials. P300 potentials were recorded during a task designed to elicit subcomponents with frontal (P300a) and both frontal and non-frontal (P300b) generators. Analyses revealed greater frontal P300a latencies among the 102 HIV-1 seropositive versus the 68 seronegative participants. In addition, frontal P300a latency was further increased by a synergistic interaction of HIV-1 serostatus with a body mass index (BMI) ≥ 25 kg/m 2. A history of substance abuse/dependence did not alter these changes. However, it did combine with HIV/AIDS to produce a smaller P300a amplitude than was seen in participants with neither disorder. The findings suggest that white matter changes accompanying an excess BMI may exacerbate those that attend HIV/AIDS and thereby slow down frontal brain function. Substance abuse, likewise, interacts with HIV/AIDS but may impair frontal brain function via a different mechanism.