There is little evidence comparing treatment outcomes between adolescents and other age groups, particularly in resource-limited settings. A retrospective analysis of data from seven HIV clinics across urban Gauteng (n=5) and rural Mpumalanga (n=2), South Africa was conducted. The analysis compared HIV-positive antiretroviral treatment (ART)-naive young adolescents (10-14 years), older adolescents (15-19), and young adults (20-24 years) to adults (≥25 years) initiated onto standard first-line ART between April 2004 and August 2010. Log-binomial regression was used to estimate relative risk (RR) of failure to suppress viral load (≥400 copies/ml) or failure to achieve an adequate CD4 response at 6 or 12 months. The effect of age group on virological failure, mortality, and loss to follow-up (LTFU; ≥90 days since scheduled visit date) was estimated using Cox proportional hazards models. Of 42,427 patients initiating ART, 310 (0.7%) were young adolescents, 342 (0.8%) were older adolescents, and 1599 (3.8%) were young adults. Adolescents were similar to adults in terms of proportion male, baseline CD4 count, hemoglobin, and TB. Compared to adults, both older adolescents (6 months RR 1.75 95% CI 1.25-2.47) and young adults (6 months RR 1.33 95% CI 1.10-1.60 and 12 months RR 1.64 95% CI 1.23-2.19) were more likely to have an unsuppressed viral load and were more likely to fail virologically (HR 2.90 95% CI 1.74-4.86; HR 2.94 95% CI 1.63-5.31). Among those that died or were LTFU, the median time from ART initiation until death or LTFU was 4.7 months (IQR 1.5-13.2) and 10.9 months (IQR 5.0-22.7), respectively. There was no difference in risk of mortality by age category, compared to adults. Young adolescents were less likely to be LTFU at any time period after ART initiation (HR 0.43 95% CI 0.26-0.69) whereas older adolescents and young adults were more likely to be LTFU after ART initiation (HR 1.78 95% CI 1.34-2.36; HR 1.63 95% CI 1.41-1.89) compared to adults. HIV-infected adolescents and young adults between 15 and 24 years have poorer ART treatment outcomes in terms of virological response, LTFU, and virological failure than adults receiving ART. Interventions are needed to help improve outcomes and retention in care in this unique population.