AIM: To compare the efficacy and tolerability of S-pantoprazole (20 mg once a day) versus racemic Pantoprazole (40 mg once a day) in the treatment of gastroesophageal reflux disease (GERD).METHODS: This multi-centre, randomized, double-blind clinical trial consisted of 369 patients of either sex suffering from GERD. Patients were randomly assigned to receive either one tablet (20 mg) of S-pantoprazole once a day (test group) or 40 mg racemic pantoprazole once a day (reference group) for 28 d. Patients were evaluated for reduction in baseline on d 0, GERD symptom score on d 14 and 28, occurrence of any adverse effect during the course of therapy. Gastrointestinal (GI) endoscopy was performed in 54 patients enrolled at one of the study centers at baseline and on d 28.RESULTS: Significant reduction in the scores (mean and median) for heart burn (P ＜ 0.0001), acid regurgitation (P ＜ 0.0001), bloating (P ＜ 0.0001), nausea (P ＜ 0.0001)and dysphagia (P ＜ 0.001) was achieved in both groups on d 14 with further reduction on continuing the therapy till 28 d. There was a statistically significant difference in the proportion of patients showing improvement in acid regurgitation and bloating on d 14 and 28 (P = 0.004for acid regurgitation; P = 0.03 for bloating) and heart burn on d 28 (P = 0.01) between the two groups, with a higher proportion in the test group than in the reference group. Absolute risk reductions for heartburn/acid regurgitation/bloating were approximately 15% on d 14 and 10% on d 28. The relative risk reductions were 26%-33% on d 14 and 15% on d 28. GI endoscopy showed no significant difference in healing of esophagitis (P= 1) and gastric erosions (P = 0.27) between the two groups. None of the patients in either group reported any adverse effect during the course of therapy.CONCLUSION: In GERD, S-pantoprazole (20 mg) is more effective than racemic pantoprazole (40 mg) in improving symptoms of heartburn, acid regurgitation,bloating and equally effective in healing esophagitis and gastric erosions. The relative risk reduction is 15%-33%.Both drugs are safe and well tolerated.