Aim: To compare the effectiveness of once-daily triple therapy with conventional triple therapy for the eradication of H. pylori. Materials and methods: A prospective comparative study in the gastroenterology unit of a tertiary care hospital was conducted for 6 months. 180 patients with active peptic disease tested positive for rapid urease test or 13C-UBT and concomitantly positive for anti-H. pylori antibodies IgG and IgM were given either once-daily (Tinidazole 1000 mg+Azithromycin 500 mg+Rabeprazole 40 mg) or twice-daily (Amoxicillin 500 mg+Clarithromycin 500 mg+Esomeprazole 40 mg) first-line therapy for ten days. Ten weeks after the completion of therapy rapid urease test and 13C-UBT were repeated. Adherence and adverse events were evaluated using pill count, structured questionnaires, and exit interviews. Results: The patient compliance was found to be better in the once-daily group (84.8%) when compared to the twice-daily group (68.8%). However, after treatment with the once-daily regimen, 74.6% of the subjects were tested negative for H. pylori and showed symptomatic relief. Whereas, with the conventional regimen, 68.7% of the subjects were tested negative for RUT and showed symptomatic relief (p=0.4063). Conclusion: We found that there was no significant difference in the eradication rates between both regimens. However, the once-daily regimen resulted in better medication compliance than the conventional regimen, suggesting that it can be considered as a safe and well-tolerated alternative to conventional triple therapies, especially for non-compliant patient groups. Further studies should be performed to confirm the results.