BACKGROUND & AIMS: Patients with functional esophageal disorders present with symptoms of chest pain, heartburn, dysphagia, or globus in the absence of any structural abnormality. Visceral hypersensitivity is a feature of these functional disorders, and might be modulated by antidepressant therapy. We evaluated evidence for the efficacy of antidepressant therapy for symptoms associated with esophageal visceral hypersensitivity in patients with functional esophageal disorders or gastroesophageal reflux disease (GERD). METHODS: We performed a systematic search of the Cochrane Comprehensive Trial Register, MEDLINE, and EMBASE (through February 2014). We analyzed relevant randomized, placebo-controlled trials reporting the effect of antidepressant therapy on experimentally induced esophageal sensation or intensity, or frequency of heartburn, chest pain, dysphagia, or globus. RESULTS: The search strategy identified 378 articles; 15 described randomized controlled trials that were eligible for inclusion. In addition, 1 conference abstract and 2 case reports were included, providing the best available evidence on specific symptoms. Esophageal pain thresholds increased by 7% to 37% after antidepressant therapy. Antidepressant therapy reduced functional chest pain over a range from 18% to 67% and reduced heartburn in patients with GERD over a range of 23% to 61%. One study included patients with globus and none of the studies included patients with functional heartburn or functional dysphagia. CONCLUSIONS: Based on a systematic review, antidepressants modulate esophageal sensation and reduce functional chest pain. There is limited evidence that antidepressants benefit a subgroup of patients with GERD. More controlled trials are needed to investigate the effects of antidepressants on functional esophageal disorders.