AIM: To compare the effectiveness of triple, standard quadruple and ampicillin-sulbactam-based quadruple therapies for H pylori eradication in a comparative threearmed randomized clinical trial. METHODS: A total of 360 H pylori-positive patients suffering from dyspepsia and aging 24-79 years with a median age of 42 years were enrolled in the study and randomly allocated into the following three groups: group A (n = 120) received a standard 1-wk triple therapy (20mg omeprazole b.I.d., 1000 mg amoxicillin b.I.d., 500 mg clarithromycin b.I.d.); group B (n = 120) received a 10-d standard quadruple therapy (20 mg omeprazole b.I.d., 1000 mg amoxicillin b.I.d., 240 mg colloidal bismuth subcitrate b.I.d., and 500 mg metronidazole b.I.d.); group C (n = 120) received the new protocol, I.e. 375 mg sultamicillin (225 mg ampicillin plus 150 mg sulbactam) b.I.d. (before breakfast and dinner), instead of amoxicillin in the standard quadruple therapy for the same duration. Chi-square test with the consideration of P ＜ 0.05 as significant was used to compare the eradication rates by intention-to-treat and per-protocol analyses in the three groups. RESULTS: The per-protocol eradication rate was 91.81% (101 patients from a total of 110) in group A, 85.84% (97patients from a total of 113) in group B, and 92.85% (104 patients from a total of 112) in group C. The intentionto-treat eradication rate was 84.17% in group A, 80.83% in group B, and 86.67% in group C. The new protocol yielded the highest eradication rates by both per-protocol and intention-to-treat analyses followed by the standard triple and quadruple regimens, respectively. However, the differences were not statistically significant between the three groups. CONCLUSION: The results of this study provide further support for the equivalence of triple and quadruple therapies in terms of effectiveness, compliance and sideeffect profile when administered as first-line treatmentfor Hpylori infection. Moreover, the new protocol using ampicillin-sulbactam instead of amoxicillin in the quadruple regimen is a suitable first-line alternative to be used in regions with amoxicillin-resistant H pylori strains.