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Long-term studies of tolerance to perinatal exposure to antiretroviral nucleoside reverse transcriptase inhibitors are required, in view of the potential genotoxicity of some of these molecules.To evaluate the incidence of cancers in uninfected children born to HIV-infected mothers.Cancers were detected in a nationwide prospective cohort of children born to HIV-infected mothers by standardized questionnaire during the prospective follow-up period of 2 years; thereafter, they were detected by spontaneous pharmacovigilance declaration and by crosschecking data with the national registries of childhood cancer. Standardized incidence ratio for incidence comparisons with general population.Ten cases of cancer were detected among the 9127 exposed HIV-uninfected children (median age: 5.4 years, 53 052 person-years of follow-up). The overall incidence did not differ significantly from that expected for the general population: 10 cases observed versus 8.9 and 9.6 expected depending on whether 1990–1999 or 2000–2004 national rates were used as reference [standardized incidence ratio of 1.1 (0.3–1.5) and 1.0 (0.5–1.9)]. Five cases of central nervous system cancer were observed (standardized incidence ratio of 3.1 [1.0–7.2] P = 0.05 and 2.4 [0.8–5.6], P = 0.12). The relative risk of cancer for children exposed to didanosine–lamivudine combination was higher than that for zidovudine monotherapy [hazard ratio: 13.6 (2.5–73.9)].This study did not evidence an overall increase in cancer risk in nucleoside reverse transcriptase inhibitor exposed children until 5 years of age. Results suggesting associations with specific nucleoside reverse transcriptase inhibitor combinations need further investigations. A longer surveillance, including differential analysis of the different cancer sites and various nucleoside reverse transcriptase inhibitors administered is warranted.