Objective To investigate the efficacy of pantoprazole and omeprazole as part of triple therapy in treatment of duodenal ulcer. Methods Seventy-eight patients with duodenal ulcer and HP-positive were randomized to two groups. A random number table was used to generate random sequence. The sequence was not concealed. No blinding was used. Thirty-nine patients received pantoprazole 40 mg + amoxicillin 1.0 g + clarithromycin 0.5 g (PAC group) and 39 patients received omeprazole 20 mg + amoxicillin 1.0 g + clarithromycin 0.5 g (OAC group), twice daily with duration of 7 days. The follow-up time was 4 to 6 weeks. Results At the end of the treatment, 38 patients completed the study, and 1 patient lost to follow-up in the PAC group; thirty-seven patients completed the study, two patients lost to followup in the OAC group. The results of intention-to-treat analysis and per-protocol analysis showed that the HP eradication rates were 87.2%/89.5% in the PAC group and 87.2%/91.9% in the OAC group (P＞0.05); the clinical improvement rates were 79.4%/81.6% in the PAC group and 82.0%/86.5% in the OAC group (P＞0.05). The side effect rates were 10.6% in the PAC group and 8.1% in the OAC group (P＞0.05). No significant difference was found between the two groups (P＞0.05). Conclusions The PAC group is therapeutically effective for eradication of HP and improves symptoms and has an equivalent effect to OAC group for patients with HP-positive duodenal ulcer. Both drugs are well tolerated.