SummaryBackground Cyclic vomiting syndrome in adults is a disorder characterized by recurrent and stereotypic episodes of severe nausea and vomiting separated by symptom‐free periods.Aims To investigate the demographic and clinical characteristics of adult cyclic vomiting syndrome patients not responding to standard tricyclic antidepressant (TCA) therapy.Methods A total of 132 adults (62 men) with cyclic vomiting syndrome were followed for a mean of 1.6 years. Of these, 17 (eight men) patients were identified as nonresponders based on the criteria of unchanged, increased or minimally changed (<25%) frequency/duration of episodes and/or emergency department visits/hospitalizations. Demographic and clinical characteristics at baseline and annually up to 4 years were investigated.Results The nonresponders were receiving TCAs at an average dose of 90 mg/day compared to a mean dose of 85 mg/day in responders. Compared with the responders, the nonresponders were significantly more likely to have a history of migraine (P < 0.05); co‐existing psychological disorders (P < 0.05); chronic marijuana use (P < 0.05) and reliance on narcotics for pain control between cyclic vomiting syndrome episodes (P < 0.05).Conclusions (1) Nonresponse to standard therapy in adult cyclic vomiting syndrome patients occurs in approximately 13% and is not explained by under dosing with TCA therapy. (2) The main risk factors for nonresponse are: co‐existing migraine headache, psychiatric disorder, chronic narcotic and marijuana use, which should be addressed aggressively when symptom exacerbations continue during attempts to induce remission in cyclic vomiting syndrome with high‐dose TCA therapy.Aliment Pharmacol Ther 31, 295–301