Gastroesophageal reflux (GER) occurs in 22-66% of patients with noncardiac chest pain (NCCP). Although open-label investigations have shown beneficial effects of antireflux therapy in NCCP, no double-blind, prospective, placebo-controlled studies have been conducted. The purpose of this study was to evaluate the effects of omeprazole compared to placebo in a prospective, double-blind, randomized trial of patients with NCCP and GER. Thirty-six consecutive patients with NCCP and GER documented by 24-hr ambulatory pH testing entered this study. The subjects were randomized to omeprazole, 20 mg by mouth twice a day (17 patients), or placebo (19 patients) for eight weeks. Patients on omeprazole obtained significantly more improvement in the fraction of chest pain days (P = 0.006) and severity (P = 0.032) when compared to placebo. More patients in the omeprazole group reported improvement in individual daily pain scores (81% vs 44%, P = 0.03) and individual severity scores (81% vs 50%, P = 0.057). Thirteen (81%) of the subjects in the treatment arm reported overall symptomatic improvement versus one (6%) in the placebo group (P = 0.001). The results of this study indicate that acid suppression with omeprazole effectively improves chest pain in patients with NCCP and GER.