Summary Background Whether 10‐day or 14‐day sequential therapy is superior to 14‐day triple therapy in the first‐line treatment of Helicobacter pylori remains controversial. Aim To compare the efficacy of 10‐day or 14‐day sequential therapy vs. 14‐day triple therapy. Methods Randomised controlled trials (RCTs) comparing 10‐day or 14‐day sequential therapy and 14‐day triple therapy as first‐line treatment in adults were searched from the PubMed and Cochrane databases from 2000 to October 2015. s from international annual conferences were also searched. The primary and secondary outcomes were the eradication rate according to the intention‐to‐treat analysis and adverse effects, respectively. Results Of the 109 articles identified, 13 RCTs including 2749 patients in the sequential therapy group and 2424 patients in the 14‐day triple therapy group were eligible. Overall, sequential therapy for 10 or 14 days was not significantly superior to 14‐day triple therapy Risk ratio (RR) 1.04, 95% confidence interval (CI) 0.99–1.08, P = 0.145. However, there was significant heterogeneity (I2 = 57.6%, P = 0.005). In the subgroup analysis of four trials, we found that 14‐day sequential therapy was significantly more effective than 14‐day triple therapy (RR: 1.09, 95% CI: 1.04–1.16, P = 0.002), and there was no significant heterogeneity (I2 = 0%, P = 0.624) in this comparison. Sequential therapy given for 10 days was not superior to 14‐day triple therapy (RR: 1.03, 95% CI: 0.98–1.09, P = 0.207). There was no significant difference in the risk of adverse effects. Conclusion Sequential therapy given for 14 days, but not 10 days, was more effective than 14‐day triple therapy as first‐line treatment.