Background: Acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) is an important health concern worldwide, and AIDS-related morbidity and mortality have seen a sharp decline due to the introduction of highly active antiretroviral therapy (HAART). To address the problems of high cost, poor compliance, lack of awareness, social stigma, and occurrence of adverse effects in India, National AIDS Control Organization (NACO) has organized a simplified drug regimen with regular monitoring, counseling, and follow-up by specially trained personnel with necessary laboratory facilities and infrastructure. Objectives: The present study was taken up to assess the efficacy of the NACO-recommended HAART regimen in subjects with HIV in the south Indian population. Materials and Methods: HAART, consisting of two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor, was instituted in 158 properly selected subjects. The initial therapy in most of the subjects was zidovudine (AZT)+lamivudine (3TC)+nevirapine (NVP). AZT was substituted by stavudine (d4T) in patients with Hb %o8 g, whereas NVP was substituted by efavirenz (EFV) in the event of non-availability, adverse effects, or possible interactions. All subjects received cotrimoxazole prophylaxis. Patients were monitored at regular intervals for 24 weeks. Efficacy was assessed by response based on CD4 count; total lymphocyte count; and improvement assessed in terms of general health, weight gain, functional status, and improvement in WHO clinical staging. Results: There was good clinical improvement with increase in CD4 count in the majority of the subjects. Antiretrovirals were well tolerated, with only mild, tolerable, and controllable adverse events, and death occurred only in 5.71% the subjects. Conclusion: The NACO-sponsored HAART regimen was found to be effective and well tolerated in the majority of the subjects, with minimum and tolerable adverse effects.