Medications that act on the central nervous system are frequently used in people infected with human immunodeficiency virus (HIV). Actually, drug interactions are an important factor in the treatment of patients with (HIV) infection and because of the complexity of the current drug regimens, clinicians should be trained in order to recognize and manage drug interactions. Herein, we present an HIV infected male admitted for manic behavior and treated with risperidone who developed a profound coma secondary to increased levels of risperidone because of a possible drug interaction with ritonavir and indinavir. Subsequently, we discuss this interaction, rarely described in the literature. Risperidone is a cytochrome P450 (CYP2D6) enzyme substrate and weak inhibitor and a CYP3A4 substrate. Possible interactions with CYP2D6 inhibitors (amiodarone, fluoxetine or ritonavir) and CYP3A4 inhibitors (indinavir and ritonavir) can increase its serum concentrations and produce significant adverse effects. In conclusion, this drug combination should be administered with caution and routinely examined for signs and symptoms of risperidone toxicity. Dosages should be reduced as needed. Finally, we think that in patients taking multiple medications, plasma levels of risperidone should be monitored especially if drug interactions are possible.