BACKGROUND Immune reconstitution inflammatory syndrome (IRIS) after initiating highly active antiretroviral therapy (HAART) has not been widely studied in children, especially in resource-poor settings. METHODS Retrospective cohort study of HIV-infected children initiating HAART between 2001 and 2006 at a tertiary pediatric hospital in Lima, Peru. Charts were reviewed for 1 year after HAART initiation. IRIS was defined as a HAART-associated adverse event caused by an infectious or inflammatory condition in patients with documented virologic or immunologic success. RESULTS Ninety-one children (52% female) received HAART for at least 1 year. Median age at initiation was 5.7 years; 91% were ART naive and 73% had CDC stage C disease. The incidence of IRIS was 19.8 events per 100 person years (95% CI: 11.5-28.0). Median time to IRIS was 6.6 weeks after HAART initiation (range: 2-32 weeks). There were 18 IRIS events, 11 unmasking and 7 paradoxical. These included associations with Mycobacterium tuberculosis in 4 cases, Bacillus Calmette Guerin lymphadenitis in 1 case, varicella zoster virus in 6 cases and herpes simplex labialis in 6 cases. Children who developed IRIS had a higher baseline HIV viral load (P = 0.02) and an indicator of malnutrition (P = 0.007) before HAART initiation. CONCLUSIONS IRIS occurred in 20% of HIV-infected children starting HAART in Peru and was associated with more advanced disease and malnutrition. Future research is needed to examine specific risk factors associated with pediatric IRIS to allow prompt identification and treatment of IRIS.