Cocaine is reported to be immunotoxic. The biochemical mechanisms responsible for the immunopharmacological outcomes of cocaine in vivo and in vitro remain, however, to be fully elucidated. Our experimental data confirm that exposure of normal human T cells to micromolar concentrations of cocaine modulates T-cell responses to stimulation by a variety of stimuli, and indicate that cocaine impairs early activation events during CD4+ but not CD4- T-cell stimulation. Pre-incubation of enriched CD4+ T-cell subpopulations that express the homing receptor CD62L with nanomolar concentrations of the endogenous opioid peptide beta-endorphin leads to a more severe impairment of activation than that noted following pre-incubation with micromolar concentrations of cocaine alone. These findings begin to elucidate the molecular and cellular mechanisms of the immunopathology of cocaine. Our data support the proposition that cocaine abuse may place cocaine-abuser HIV-seropositive individuals at increased risk of opportunistic infections.