HIV-infected children in resource-limited settings are increasingly gaining greater access to highly active antiretroviral therapy (HAART) but documented longitudinal data remains limited. We aimed to study the clinical and immunological outcomes among 67 South Indian HIV-infected children with >18 months of follow-up on HAART at a tertiary HIV care program. The median CD4 cell count at enrolment was 290 cells microl(-1) and at treatment initiation was 225 cells microl(-1). Patients demonstrated a significant rise in their CD4 cell counts between treatment initiation and after 6 months (701 cells microll(-1); p = 0.007), 12 months (741 cells microl(-1); p = 0.037), and 18 months of therapy (718 cells microl(-1); p = 0.005). The most common adverse events to therapy were nausea (20.9%) and rash (25.4%). Over one-fifth of patients (25.4%) substituted therapy due to toxicities and 19.4% of patients switched to second-line protease inhibitor-containing regimens. In this South Indian pediatric cohort, generic HAART was safe, effective and relatively well tolerated.