To date, no randomized trials have compared the efficacy of 7-day vonoprazan, amoxicillin, and metronidazole triple therapy (VAM) versus 7-day vonoprazan, amoxicillin, and clarithromycin triple therapy (VAC) as a first-line treatment for Helicobacter pylori eradication. This study was performed to compare the efficacy of VAM and VAC as first-line treatments. This prospective multicenter randomized trial was performed in Japan and involved 124 H. pylori-positive patients without a history of eradication. Patients without antibiotic resistance testing of H. pylori were eligible. The patients were randomized to receive either VAC (vonoprazan 20 mg + amoxicillin 750 mg + clarithromycin 200 or 400 mg twice a day) or VAM (vonoprazan 20 mg + amoxicillin 750 mg + metronidazole 250 mg twice a day) for 7 days, with stratification by age and sex. Eradication success was evaluated using the 13C-urea breath test. We evaluated safety using patient questionnaires (UMIN000025773). The intention-to-treat and per-protocol eradication rates of VAM were 91.3% (95% confidence interval [CI], 82.0-96.7%) and 92.6% (95% CI, 83.7-97.6%), respectively, and those of VAC were 89.1% (95% CI, 77.8-95.9%) and 96.1% (95% CI, 86.5-99.5%), respectively. No significant difference was observed between VAM and VAC in either analysis (P = 0.76 and P = 0.70, respectively). Abdominal fullness was more frequent in patients who received VAM than VAC. These findings suggest that VAM as a first-line treatment in Japan can be categorized as grade B (intention-to-treat cure rate of 90-95%) and have potential as a first-line national insurance -approved regimen.