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Background: Sequential and concomitant therapies are two innovative therapies for Helicobacter pylori ( H. pylori) eradication. However, the comparative efficacy and safety of these treatments are controversial. Therefore, we aimed to conduct an updated systematic review and meta-analysis of studies that compared these two treatments. Methods: A search of PubMed, Embase, the Cochrane Library, and Web of Science was carried out. Randomized controlled trials (RCTs) that compared sequential with concomitant therapies were selected for meta-analysis. Results: Twenty RCTs were included in the analysis. The eradication rate of 10-day sequential therapy was superior to that of 5-day concomitant therapy (82.09 versus 77.79%, relative risk (RR) 1.052 (95% confidence interval (CI) 1.004-1.103), P = 0.035)), similar to that of 7-day concomitant therapy (82.40 versus 86.99%, RR 0.959 (95% CI 0.874-1.053), P = 0.382), and inferior to that of 10-day concomitant therapy (78.39 versus 83.32%, RR 0.945 (95% CI 0.907-0.984, P = 0.006); the occurrence of diarrhea was higher in 10-day concomitant therapy than that in 10-day sequential therapy. Compared with the eradication rate of sequential therapy, that of concomitant therapy was higher in metronidazole-resistant strains (RR 0.912 (95% CI 0.844-0.986, P = 0.020)) and strains resistant to metronidazole and clarithromycin (RR 0.542 (95% CI 0.308-0.956, P = 0.035)). Conclusion: The efficacy of concomitant therapy was duration dependent, and 10-day concomitant therapy was superior to 10-day sequential therapy. Compared to sequential therapy, concomitant therapy was more efficacious for metronidazole-resistant strains and metronidazole plus clarithromycin-resistant strains. However, diarrhea was more frequent with concomitant therapy than with sequential therapy. [ABSTRACT FROM AUTHOR]