OBJECTIVES: An 8-week course of proton pump inhibitors (PPIs) is the therapy of choice for the treatment of gastroesophageal reflux disease (GERD). Esomeprazole, the S-isomer of omeprazole, seems to have more potent acid suppression compared to other PPIs due to improved pharmacokinetic profile. The aim of the current systematic review was to identify consistent evidence of differences in efficacy between esomeprazole and the other available PPIs. METHODS: A literature search of Medline, Embase and Cochrane Library was conducted (last search 8/2014) to identify randomized clinical trials comparing rates of endoscopic healing and heartburn resolution with esomeprazole versus other PPIs (i.e. lansoprazole, omeprazole and pantoprazole) in the treatment of GERD. Search and selection of the studies was performed independently by two researchers. Only intention-to-treat population reported data were analyzed. RESULTS: Twelve RCT studies (3 vs omeprazole, 3 vs lansoprazole and 6 vs pantoprazole) met the inclusion criteria and were included in the systematic review. Almost all identified studies had low or moderate risk of bias (Jadad scale ranging 3-5). One study had high risk of bias. The analysis comparing esomeprazole 40 mg with lansoprazole 30 mg showed a significant difference in endoscopic healing rate in favor of esomeprazole at 4 weeks (OR=1.25; 95%CI: 1.12-1.40) and 8 weeks (OR=1.29; 95%CI: 1.13-1.48). Similarly, esomeprazole 40 mg demonstrated significantly higher healing rate when was compared with pantoprazole 40 mg at 4 weeks (OR=1.33; 95%CI: 1.15-1.52) and with omeprazole 20 mg at 8 weeks (OR=1.56; 95%CI: 1.08-2.25). Data from meta-analysis indicated that esomeprazole 40 mg provided also a greater proportion of patients with sustained resolution of heartburn for up 4 weeks than omeprazole 20 mg (OR=1.34; 95%CI: 1.09-1.65). The tolerability and safety of esomeprazole were comparable to that of other PPIs. CONCLUSIONS: Esomeprazole proved to be more effective in healing of erosive GERD than the other available PPIs.