Purpose: Cyclic vomiting syndrome (CVS) is a disorder characterized by recurrent and stereotypic episodes of severe nausea and vomiting separated by symptom-free periods. It is now diagnosed more in adults than children. It's recurrent and disabling character requires more preventive and therapeutic options to reduce emergency department (ED) visits and hospitalizations and improve quality of life in these patients. Methods: In an open labelled study of 45 patients diagnosed with CVS based on Rome III criteria, we investigated the long term efficacy of tricylclic antidepressant (TCA) alone or in combination with Propranolol or Keppra on frequency and duration of CVS episodes and frequency of ED visits or hospitalizations during one and two years follow up. All received detailed information about the disorder, psychological support and help in identifying the trigger events as well as standard back ground support with Alprazolam for anxiety, Dicyclomine for abdominal pain and Promethazine for back up nausea. Demographic data, TCA dosage, duration and frequency of CVS episodes, ED visits and hospitalizations and subjective global assessment at baseline and during TCA therapy were recorded. Adverse effects with TCA were monitored. 5 stopped the medication, 2 within 3 months and 1 after 12 months, as their symptoms had completely resolved, 1 because of a lack of response and 1 due to severe hallucinations. Results: The results are summarized in Table. We followed 40 patients (19 female), mean age 35 years (18–63) on TCA and or TCA plus Keppra (N = 1) or Propranolol (N = 1) for one year and 23 for two years. 37 were on amitriptyline, 2 on nortriptyline and 1 on doxepine. Mean age of symptoms onset was 26 years and 32 years for making the diagnosis of CVS. The goal dose of TCA was 1 mg/kg and the actual doses achieved were 25–200 mg (average 90 mg, qhs). Side effects were reported in 35 percent of our patients and included: dry mouth, somnolence, constipation, postural hypotension, chronic fatigue, blurred vision, and mild hallucinations. 86 percent reported an improved quality of life by subjective global assessment.Table: Effect of Tricyclic Antidepressant therapy on Cyclic Vomiting Syndrome Charecteristics.Conclusion: Long-term TCA therapy significantly reduces the frequency and duration of CVS episodes, ED visits & hospitalizations and improves quality of life. (P < 0.05) These data indicate that TCAs are the treatment of choice for adult CVS patients. Their efficacy could be explained by the hypothesized role of the brain-gut axis in the pathogenesis of this disorder.