Objectives: Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder with no certain treatment. We aimed to compare the efficacy of amitriptyline and topiramate on prophylactic therapy of CVS.Materials and Methods: This is a randomized clinical trial conducted during 2016 in Isfahan, Iran. The inclusion criteria were CVS patients (based on Rome III) aging 3-15 years with normal physical examination, no metabolic disorder, and no gastrointestinal obstruction or renal impairment. Recruited patients were divided into two groups of amitriptyline (1 mg/kg/daily) and topiramate (1-2mg/kg/daily) and were followed 3-months. The outcome was evaluated by comparing severity of attacks (monthly frequency and duration of attacks) before and after intervention.Results: Thirty-six children entered each group and two patients left the amitriptyline group. Patients and disease characteristics were similar between groups before intervention (P-value>0.05). The frequency of attacks (standard deviation) after intervention in amitriptyline and topiramate group were 0.91 (0.40) and 1.07 (0.55), respectively (P-value=0.368) and the duration of attacks (SD) after intervention were 3.43 (2.46) and 4.90 (3.03), respectively (P-value=0.017). Twenty-three patients (68%) in amitriptyline group and 14 patients (39%) in topiramate group stopped having attacks after intervention (P-value=0.016).Conclusion: Amitriptyline can be considered as the better choice for CVS therapy compared to topiramate considering the high response rate of patients to this drug
