Background and Aim There is little published research to examine the best approach to the management of Helicobacter pylori in Myanmar. This study aimed to determine the relative efficacy and tolerability of sequential eradication therapy compared to Myanmar's current recommendation of a concomitant four drug regimen. Methods Patients were screened for H. pylori using monoclonal Stool Antigen Testing (SAT). Those testing positive were randomized 1:1 to receive receive Myanmar's first‐line regimen of 14 days of concomitant rabeprazole, clarithromycin, amoxycillin and tinidazole (140 pills, cost US$23) or 10 days of sequential rabeprazole, clarithromycin, amoxycillin and tinidazole (60 pills, cost US$10). Adherence and adverse effects were recorded, and the efficacy of the regimens assessed with repeat SAT. Results Of the 1011 patients screened for H. pylori infection, 313 (31%) tested positive. There was no statistical difference in the cure rates of the two regimens in either intention‐to‐treat: 128/157 (82%; 95% confidence interval (CI): 75–87%) receiving sequential therapy versus 123/156 (79%; 95% CI: 72–85%) receiving concomitant therapy (P = 0.55) or per‐protocol analysis: 125/131 (95%; 95% CI: 90–98) receiving sequential therapy versus 121/130 (93%; 95% CI: 87–96) receiving concomitant therapy (P = 0.42). Side effects of therapy were reported in 54/157 (47%) patients taking sequential therapy compared with 62/156 (53%) taking concomitant therapy, but this difference did not reach statistical significance (P = 0.33). Conclusions In this high‐burden, resource‐poor setting, less expensive sequential therapy was as effective and as well tolerated as the currently recommended concomitant four drug regimen for eradication of H. pylori.