©2016 International Medical Press. Background: The National Access to Antiretroviral Program for People Living with HIV/AIDS was launched in Thailand in 2002. HIV-infected, antiretroviral-naive, severely immunosuppressed children were initiated on highly active combination antiretroviral treatment (cART). This study aimed to determine the long-term effectiveness of cART. Methods: Data were extracted from medical records. Primary end points were mortality rate, proportion of children who remained on first-line cART regimen and children with plasma HIV RNA level (pVL) < 50 copies/ml at week 520. Results: From August 2002 to July 2003, 107 children were enrolled. The baseline median age was 7.6 years (IQR 5.7-10.0), the median CD4 + T-cell count was 60 cells/mm 3 (IQR 21-272) and the median pVL was 5.37 log 10 copies/ml (IQR 5.01-5.76). The mortality rate during and after the first year was 3.7 and 0.006 deaths/100 person-years, respectively. At week 520, 90 (84%) continued to be actively followed. Their median age was 17.8 years (IQR 15.8-19.8). 73 (81% as-treated) remained on the first-line regimen, while 18 (20%) had switched to a second-line cART regimen, at the median time of 272 weeks (IQR 256-363) after the first-line cART initiation. 69 (77%) had pVL < 50 copies/ml and the median CD4 + T-cell count was 636 cells/mm 3 (IQR 466-804). 83 (92%) and 64 (71%) had CD4 + T-cell counts ≥200 and > 500 cells/mm 3 , respectively. Conclusions: Long-term virological control, favourable immunological outcomes and healthy survival was achieved in severely immunosuppressed, perinatally HIV-infected children who started first-line NNRTI-based cART. Continuing surveillance for long-term complications is warranted.