To evaluate the efficacy of members of the H2RA family for the treatment of gastro-esophageal reflux disease (GERD). We performed a thorough electronic search on PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) for eligible randomized clinical trials that investigated H2RAs and the treatment of GERD up to July 28, 2015. A comprehensive network meta-analysis was conducted to compare the effects of each subset of H2RAs. A total of 13 randomized controlled trials (RCTs) were included in our network meta-analysis. Our results showed that, compared with placebos, H2RAs were more effective for the treatment of GERD. Within the H2RA family, famotidine 80 mg per day (OR = 0.17, 95% CI: 0.06 - 0.38) was determined to be the most effective, followed by famotidine 40 mg per day (odds ratio (OR) = 0.23, 95% confidence interval (CI), 0.11 - 0.44); ranitidine 1,200 mg per day (OR, 0.32; 95% CI, 0.13 - 0.63); ranitidine 600 mg per day (OR, 0.27; 95% CI, 0.14 - 0.47); ranitidine 300 mg per day (OR, 0.31; 95% CI, 0.15 - 0.55); cimetidine 1,600 mg per day (OR, 0.36; 95% CI, 0.14 - 0.73); nizatidine 600 mg per day (OR, 0.58; 95% CI, 0.24 - 1.24); and finally nizatidine 300 mg per day (OR, 0.61; 95% CI, 0.25 - 1.26). The placebo was determined to be the least effective treatment. Compared with other H2RAs, famotidine had the best short-term therapeutic effect in adults with GERD, especially at a dosage of 80 mg per day.