Objectives: The study compares rates of protease inhibitor (PI) use during the 3 years following the introduction of these newer treatments among human immunodeficiency virus (HIV)-infected individuals with and without serious mental illness and examines persistence of use of these therapies across these subgroups. Method: We used merged autoimmune deficiency syndrome (AIDS)/HIV surveillance and Medicaid claims data to examine use of PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) among New Jersey Medicaid beneficiaries with AIDS between 1996 and 1998. Based on the ICD-9-CM diagnoses assigned by a high-credibility source in 1 inpatient or 2 outpatient claims, we identified patients with schizophrenia (ICD-9-CM code 295) and those with severe affective disorder (combining patients with recurrent major depressive disorder [ICD-9-CM code 296.3] or bipolar disorder [296.4, 296.5, 296.6, 296.7, or 296.8]). These groups were compared with those patients with no serious mental illness. Results: In this sample, patients with schizophrenia (68.3%) and those with severe affective disorder (75.6%) were more likely to have initiated new antiretroviral therapy than were those without serious mental illness (64.3%). Patients with severe affective disorder, but not those with schizophrenia, were significantly less persistent (p < .01) in their use of PI/NNRTI therapy than those without serious mental illness. Conclusions: No evidence was found that the presence of a serious mental illness discourages physicians from initiating new antiretroviral therapy, perhaps reflecting a comparatively high level of integration of these patients into the health care system. Patients with schizophrenia are as persistent in their use of PI/NNRTI therapy as those without a serious mental illness. Lower rates of medication compliance by those with severe affective disorder justify increased efforts to support optimal adherence.