Abstract A significant subset of HIV-positive patients suffer from AIDS-Related Dementia Complex (ADC), an array of neurologic and neuropsychologic impairments. The HIV coat protein gp120 has been implicated in the deleterious neurologic consequences of HIV infection, damaging neurons through a glutamatergic and calcium-dependent pathway. We have previously reported that glucocorticoids, the adrenal steroids secreted during stress, can exacerbate the neurotoxic and calcium-mobilizing effects of gp120 in hippocampal and cortical cultures. Because both the symptomatology of ADC, as well as the neuropathologic profile of post-mortem HIV brains suggests an involvement of the striatum, we examined whether glucocorticoids could also augment the damaging effects of gp120 in primary striatal cultures. We observe that neither gp120 nor the glucocorticoid corticosterone, when administered alone, cause neurotoxicity or mobilization of free cytosolic calcium; however, a combination of the two caused significant toxicity and neuron death. This, along with our prior findings of gp120–glucocorticoid interactions, is striking, given the heavy clinical use of synthetic glucocorticoids for management of pulmonary complications of HIV infection.