OBJECTIVE: The objective of this study was to evaluate clinical improvement and safety with use of cyproheptadine in functional gastrointestinal disorders (FGIDs) in children. METHODS: Retrospectively evaluating the efficacy and safety of the use for indications including Rome III-defined FGIDs: functional abdominal pain, functional dyspepsia, irritable bowel syndrome (IBS), abdominal migraine, cyclic vomiting syndrome. Response categories were as follows: no improvement group/partial improvement group; requiring intervention, or complete improvement group (CIG); warranting discontinuation; ongoing use; or parental unwillingness to stop medication. RESULTS: Among 307 patients, 151 included; 58% girls, ages 1 to 18 years (median 9); 110 (72.8%) reported complete symptom improvement; 41 (27.2%) reported no or partial improvement. Mean initial and final doses in the CIG were 4.85 mg/day (0.14 mg . kg . day) and 5.34 mg/day (0.14 mg . kg . day), respectively. A total of 102/151 (68%) reported no adverse effects. Adverse effects shown were as sleepiness in 19/151 (13%) and weight gain in 15/151 (10%). Cyproheptadine was effective in improving symptoms of functional abdominal pain, functional dyspepsia, in a relatively larger number of patients. Patients in smaller numbers had significant improvement 13/18 (72%) abdominal migraine, 10/10 (100%) IBS, and 6/8 (75%) cyclic vomiting syndrome. This is the first time report of improvement in IBS. Other pharmacodynamics had been as follows: the lower the body weight, the higher are the odds of no to partial improvement; patients in no improvement group/partial improvement group experience more adverse effects as compared to the CIG; the single best predictor of clinical improvement was body mass index. A 1 unit increase in body mass index with cyproheptadine use increased the odds of clinical improvement by 1.5-fold (P = 0.01). CONCLUSIONS: Cyproheptadine effectively improves symptoms of Rome III-defined FGIDs and has a good safety profile when used for these indications.