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Little is known on the risk of cancer in HIV-positive children in sub-Saharan Africa. We examined incidence and risk factors of AIDS-defining and other cancers in pediatric antiretroviral therapy (ART) programs in South Africa.We linked the records of 5 ART programs in Johannesburg and Cape Town to those of pediatric oncology units, based on name and surname, date of birth, folder and civil identification numbers. We calculated incidence rates and obtained hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression models including ART, sex, age and degree of immunodeficiency. Missing CD4 counts and CD4% were multiply imputed. Immunodeficiency was defined according to World Health Organization 2005 criteria.Data of 11,707 HIV-positive children were included in the analysis. During 29,348 person-years of follow-up 24 cancers were diagnosed, for an incidence rate of 82 per 100,000 person-years (95% CI: 55–122). The most frequent cancers were Kaposi sarcoma (34 per 100,000 person-years) and non-Hodgkin Lymphoma (31 per 100,000 person-years). The incidence of non AIDS-defining malignancies was 17 per 100,000. The risk of developing cancer was lower on ART (HR: 0.29; 95% CI: 0.09–0.86), and increased with age at enrollment (>10 vs. <3 years: HR: 7.3; 95% CI: 2.2–24.6) and immunodeficiency at enrollment (advanced/severe versus no/mild: HR: 3.5; 95% CI: 1.1–12.0). The HR for the effect of ART from complete case analysis was similar but ceased to be statistically significant (P = 0.078).Early HIV diagnosis and linkage to care, with start of ART before advanced immunodeficiency develops, may substantially reduce the burden of cancer in HIV-positive children in South Africa and elsewhere.