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A significant proportion of children with Crohn disease develop a secondary loss of response (LOR) to infliximab. Our aim was to study the impact of initial treatment strategies on secondary LOR.We reviewed the medical records of children with Crohn disease who received scheduled maintenance infliximab therapy for at least 12 months. We compared children who developed LOR with those who did not; with regards to their clinical and laboratory parameters, disease phenotype, and treatment strategy before developing LOR.A total of 73 children (median age at diagnosis 11 (2–16) years, 41 boys) who had received a median duration of 33 (13–110) months of infliximab therapy were included in the final analysis. LOR was seen in 25(34.2%). Demographic variables, disease phenotype (age, disease location, and behavior), inflammatory parameters, and pediatric Crohn disease activity index at induction with infliximab were similar between both groups. Children with LOR had a significantly greater number of flares of the disease when compared to those who did not have LOR (4 [1–8] vs 2 [1–5] P = 0.03). The choice of the concomitant immunomodulator—methotrexate (11/29 [37.9%]) versus azathioprine (11/36 [30.5%]) (P = 0.6) did not affect LOR rates. The median time-lag between diagnosis and induction with infliximab was significantly longer in children with LOR as compared to those who did not have an LOR (28 [4–90] months vs 12.5 [1–121] months, P = 0.004).Early use of infliximab in pediatric Crohn disease is associated with a decrease in secondary LOR. The type of concomitant immunomodulator used does not make a difference to LOR rates.