Background/Aim: The primary aim of this study was to assess the efficacy of a bismuth-based quadruple regimen as first-line therapy for Helicobacter pylori (HP) eradication in diabetes mellitus (DM) patients. The secondary aim was to study the effect of HP eradication on dyspeptic symptoms in DM patients. Method: Eighty-nine consecutive type 2 DM and 48 non-diabetic age- and sex-matched patients were enrolled in this study. Diabetic patients were randomized to receive either pantoprazole (40 mg b.i.d.), clarithromycin (500 mg b.i.d.), and amoxicillin (1 g b.i.d., PCA-DM group) for 14 days, or pantoprazole (40 mg b.i.d.), bismuth citrate (400 mg b.i.d.), tetracycline (500 mg q.i.d.), and metronidazole (500 mg b.i.d., PBTM-DM group) for 14 days as the eradication regimen. All non-diabetic patients were treated by quadruple therapy (PBTM-non-DM group) for 14 days. We used the validated Leeds Dyspepsia Questionnaire (LDQ) to assess dyspeptic symptoms at baseline and 6 weeks after the end of treatment. Results: The HP eradication rates with intention-to-treat (ITT) and per-protocol (PP) analyses were 51% (for both) in the PCA-DM group; 81 and 85% in the PBTM-DM group, and 85 and 87% in the PBTM-non-DM group. The eradication rates are not different between the PBTM-DM and PBTM-non-DM groups (p > 0.05). The eradication rate was significantly lower in the PCA-DM group with both ITT and PP analysis than in the PBTM-DM and PBTM-non-DM groups (p < 0.05). LDQ score was 4.53 ± 7.7 in DM patients with successful eradication and 14.68 ± 5.9 in DM patients without successful eradication (p < 0.05). Conclusion: The bismuth-based quadruple eradication regimen as first-line therapy is safe, tolerable and achieves a high cure rate in patients with DM, and successful eradication may be beneficial on dyspeptic symptoms.