BACKGROUND: No previous study of Japanese children with ulcerative colitis (UC) has reported the risk factors for intolerance of 5-aminosalicylic acid (5-ASA). We aimed to identify risk factors for intolerance of oral 5-ASA preparations in pediatric UC. METHODS: Patients with childhood-onset UC who were seen at our hospital between November 2003 and March 2020 were investigated. Intolerance of 5-ASA was defined as having clinical symptoms (pyrexia, abdominal pain, diarrhea, bloody stool) that worsened after starting oral administration of 5-ASA and improved after discontinuation of 5-ASA. Patient sex, age, body size, laboratory data, pediatric UC activity index scores, and colonoscopy-based determinations of the extent and severity of the affected lesion at initiation of 5-ASA of intolerant and tolerant groups were compared. RESULTS: Fifteen patients were in the intolerant group, and 37 were in the tolerant group. The leukocyte count, C-reactive protein level, and erythrocyte sedimentation rate were significantly higher in the intolerant group than the tolerant group; the albumin level in the intolerant group was significantly lower. All intolerant patients and 68% of tolerant patients had pancolitis (Paris classification E4). Patients with a large, affected area (Paris classifications E3 and E4) more frequently had intolerance to 5-ASA than patients with a small lesion. The cumulative Mayo endoscopic subscore (cMES), which is the sum of MES scores for six regions of the large intestine, was significantly higher in the intolerant group. CONCLUSIONS: Pediatric UC patients with more intense inflammation and a large lesion could have an increased risk of intolerance for 5-ASA.