Background: Sequential therapy (SQT) has been reported to be effective in the eradication of Helicobacter pylori (HP) infection and, if more largely validated, could become a valid alternative to standard triple therapy (STT). Aim: To evaluate efficacy and tolerability of SQT, with two different durations, in comparison to a 7-day STT. Patients & Methods: A total of 270 naive HP+ patients were randomized to receive STT (n=90), including esomeprazole (ESO) 20 mg bid, plus amoxicillin (AMO) 1000 mg bid, and clarithromycin (CLA) 500 mg bid, for 7 days; SQT for 10 days (SQT-10, n=90), including ESO 20 mg bid, for 10 days, associated with AMO 1000 mg bid for early 5 days, followed by CLA 500 mg bid, plus tinidazole (TNZ) 500 mg bid, both in the last 5 days; SQT for 8 days (SQT-8, n=90), including ESO 20 mg bid, for 8 days, associated with AMO 1000 mg bid for early 4 days, followed by CLA 500 mg bid, plus TNZ 500 mg bid, both in the last 4 days. HP status was established by the agreement of two tests out of three chosen among urea breath test, stool antigen assay, urease rapid test and histology. Tolerability of regimens was assessed by scoring the severity of symptoms reported by patients in a predefined questionnaire. Results: Eradication rates achieved by SQT-10 and SQT-8 were significantly higher than that by STT at both intention-to-treat (86% and 83% vs. 66%, p<0.02) and per-protocol analysis (87% and 90% vs. 75%, p<0.01), while no difference was found among the two SQT therapies. Mean scores of symptoms occurring on SQT-8 were significantly lower than those on SQT10 (nausea: 2.83 ± 1.90 vs. 4.68 ± 4.00, p<0.01; taste perversion: 3.14 ± 1.96 vs. 9.42 ± 6.54, p<0.05) and STT (nausea: 2.83 ± 1.90 vs. 5.08 ± 4.70, p<0.01; diarrhea: 3.14 ± 1.96 vs. 4.11 ± 4.01, p<0.02). Conclusions: SQT for 10 or 8 days are more effective than STT for HP eradication. Among SQT the 8 days regimen appears to be better tolerated than 10 days regimen.