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Background Surveillance for mid- and long-term anti-retroviral therapy (ART) toxicity in children is important for informing treatment guidelines. We assessed the safety of darunavir (DRV) and atazanavir (ATV), commonly used as second-line protease inhibitors following lopinavir/ritonavir, in Europe and Thailand.Methods Cohorts contributed individual patient data on adverse events (AE) in those aged <18 years taking DRV and ATV, respectively, to 02/2014. Rates of Division of AIDS (DAIDS) grade =3 laboratory AEs were calculated.Results Of 431 patients on DRV and 372 on ATV, 317 (74%) and 301 (81%), respectively, had weight and dose data available, of whom 56 (18%) and 33 (9%) took the drugs at a non-approved age or dose. Median age at DRV and ATV start was 14.8 years (IQR 12.8–16.1) and 13.5 years (11.4–15.2); 43% and 26% had received =8 ART drugs previously. Overall rates of grade =3 AEs for absolute neutrophils, total cholesterol, triglycerides, pancreatic amylase, lipase and alanine aminotransferase (ALT) were =3/100 person-years (PY) on approved doses of both drugs, but 66/100 PY (95% CI 52, 84) for bilirubin after <12 months on ATV declining to 32/100 PY (95% CI 23, 44) after >24 months. Five serious drug-related clinical AEs were reported in four patients on ATV (one discontinued) and three in three patients on DRV (all discontinued), and did not substantially differ in those on approved compared to non-approved doses. Proportions on the drugs at last follow-up were 89% (383/431) for DRV and 81% (301/372) for ATV (including 73/92 with grade =3 hyperbilirubinaemia).Conclusions AEs were few in number and comparable for the two drugs, with the exception of high rates of hyperbilirubinaemia for ATV; few patients discontinued due to toxicity.