Background: Clarithromycin plays an important role in eradicating Helicobacter pylori ( H. pylori) through quadruple therapy. However, there is limited research on whether different forms of clarithromycin dosage have similar efficacies against H. pylori. Objective: We aimed to evaluate the efficacy of different forms of clarithromycin dosage in bismuth-containing quadruple therapy for eradicating H. pylori. Design: A single-center retrospective analysis comparing the efficacy of different forms of clarithromycin dosage in eradicating H. pylori. Methods: An analysis was conducted on patients diagnosed with H. pylori infection through the 13C-urea breath test (13C-UBT) at Henan Provincial People’s Hospital, China from 2020 to 2022 who were treated with either a dispersible or sustained-release clarithromycin tablet (500 mg each), alongside amoxicillin (1000 mg), a standard dose of proton pump inhibitors (PPIs), and bismuth citrate (220 mg), administered twice daily as part of bismuth-containing quadruple therapy. Treatment efficacy was assessed using 13C-UBT at least 4 weeks after treatment completion. The H. pylori eradication rate was the primary outcome of this study, and factors influencing it were analyzed. Results: Among 2094 screened patients, 307 with H. pylori infection (mean age, 41.8 ± 0.7 years; 43% men) received bismuth-containing quadruple therapy. Univariate analysis of the dispersible and sustained-release tablet groups revealed a lower eradication rate with the sustained-release tablet compared with the dispersible clarithromycin tablet regimen (75.26% (73/97) vs 95.26% (200/210), respectively; p < 0.05). Other factors, such as smoking, age, and PPI type, were not significantly associated with the cure rate. Multivariate analysis identified the form of clarithromycin dosage (dispersible vs sustained-release) to be an independent risk factor for eradication failure using the bismuth-containing quadruple therapy (odds ratio = 0.145, 95% confidence interval: (0.065–0.323); p < 0.05). Conclusion: The clarithromycin dispersible tablet demonstrated a higher H. pylori eradication rate, and the sustained-release clarithromycin tablet may be inappropriate for H. pylori eradication.