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Comprehensive care of human immunodeficiency virus (HIV)-infected children in the resource-poor setting is challenging, and published reports on treatment outcomes in this setting are limited. The aim of this study was to evaluate outcomes of HIV-infected children initiated on highly active antiretroviral therapy (HAART) between April 2005 and April 2009 at a primary health-care centre in Alexandra Township, South Africa. Of the 337 patients initiated on HAART, 83% (281 of 337) were still in care at the time of analysis. The median age at initiation was five years six months [interquartile range (IQR) 2.4–8.8], with only 11% (37 of 337) less than 1 year of age. At one and two years of treatment follow-up, the mean increase in CD4% was 12.8% (8.7–17.4) and 17.9% (11.7–21.6), respectively, while 86% (172 of 199) and 88% (99 of 112) were virally suppressed. Improvement in body mass index (BMI), height-for-age (HAZ) and weight-for-age Z scores (WAZ), along with low rates of lost to follow-up (3.6%; 12 of 337) and death (2.3%; eight of 337) were encouraging. There was less recovery in HAZ in children older than 10 years. 65% (182 of 281) of children remained on their initiating regimens; however, 25% (72 of 281) required single drug substitutions for lipodystrophy. Evidence of some drug resistant strains needs addressing. There was a high tuberculosis (TB) coinfection rate, with 66% (225 of 337) having TB ever diagnosed. Thirty-two per cent (108 of 337) were orphans and many psychosocial problems were identified. We concluded that although the outcomes from this resource-limited paediatric HAART treatment programme are encouraging, awareness and appropriate management of the many co-existing challenges, by a multidisciplinary team, is very important for success. Sustained provision of HAART is essential; however, HAART alone is not enough. [ABSTRACT FROM AUTHOR]