Summary Aim This study aimed to test the efficacy of mesalazine in maintaining remission in pediatric Crohn's disease (CD) following successful flare-up treatment. Methods In this double-blind, randomized, placebo-controlled trial, 122 patients received either mesalazine 50 mg/kg per day ( n = 60) or placebo ( n = 62) for one year. Treatment allocation was stratified according to flare-up treatment (nutrition or medication alone). Recruitment was carried out over two periods, as the first period's results showed a trend favoring mesalazine. Relapse was defined as a Harvey–Bradshaw score more than or equal to 5. Time to relapse was analyzed using the Cox model. Results The one-year relapse rate was 57% ( n = 29) and 63% ( n = 35) in the mesalazine and placebo groups, respectively. We demonstrated a twofold lower relapse risk ( P < 0.02) in patients taking mesalazine in the medication stratum (first recruitment period), and a twofold higher risk in patients taking mesalazine in the nutrition stratum (second recruitment period), compared with the other groups. None of the children's characteristics, which differed across the two recruitment periods, accounted for the between-period variation in mesalazine efficacy. One serious adverse event was reported in each treatment group. Conclusion Overall, mesalazine does not appear to be an effective maintenance treatment in pediatric CD.