BACKGROUND AND AIM: Metronidazole and tetracycline-based second-line quadruple therapy, widely used for Helicobacter pylori infection, often ends up in failure due to antibiotic resistance and poor compliance in Korea. Our aim is to evaluate the efficacy and tolerability of moxifloxacin-based triple therapy as an alternative second-line treatment for H. pylori infection. METHODS: The subjects consisted of 85 patients infected with H. pylori, in whom initial proton pump inhibitor triple therapy had failed. They were randomized to receive the following 7-day therapy: 1, moxifloxacin 400 mg q.d., esomeprazole 20 mg b.i.d., and amoxicillin 1 g b.i.d.; and 2, esomeprazole 40 mg b.i.d., tripotassium dicitrate bismuthate 300 mg q.i.d., metronidazole 500 mg t.i.d., and tetracycline 500 mg q.i.d. Eradication rates, drug compliance, and side-effect rates of each group were evaluated. RESULTS: The eradication rates were 75.6 and 83.8% with moxifloxacin triple therapy, and 54.5 and 72.7% with quadruple therapy by intention-to-treat (p = .042) and per-protocol analyses (p = .260), respectively. Moxifloxacin triple therapy was significantly superior to quadruple therapy in terms of side-effect rates (p = .039). Compliance for therapy, i.e., the percentage of tablets taken (> 85%), was 90.2 and 75.0%, numerically higher in moxifloxacin triple therapy group than in quadruple therapy group, but without statistical difference (p = .065). CONCLUSIONS: Moxifloxacin-based triple therapy showed high eradication rates with few side effects and good drug compliance, suggesting this regimen could be a safe and effective option as second-line therapy for H. pylori infection in Korea.