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Use of calcium channel blockers has been found to improve sepsis outcomes in animal studies and one clinical study. This study determines whether the use of calcium channel blockers is associated with a decreased risk of mortality in patients with sepsis.Population-based matched cohort study.National Health Insurance Research Database of Taiwan.Hospitalized severe sepsis patients identified from National Health Insurance Research Database by International Classification of Diseases, Ninth Revision, Clinical Modification codes.None.The association between calcium channel blocker use and sepsis outcome was determined by multivariate-adjusted Cox proportional hazard models and propensity score analysis. To examine the influence of healthy user bias, beta-blocker was used as an active comparator. Our study identified 51,078 patients with sepsis, of which, 19,742 received calcium channel blocker treatments prior to the admission. Use of calcium channel blocker was associated with a reduced 30-day mortality after propensity score adjustment (hazard ratio, 0.94; 95% CI, 0.89–0.99), and the beneficial effect could extend to 90-day mortality (hazard ratio, 0.95; 95% CI, 0.89–1.00). In contrast, use of beta-blocker was not associated with an improved 30-day (hazard ratio, 1.06; 95% CI, 0.97–1.15) or 90-day mortality (hazard ratio, 1.00; 95% CI, 0.90–1.11). On subgroup analysis, calcium channel blockers tend to be more beneficial to patients with male gender, between 40 and 79 years old, with a low comorbidity burden, and to patients with cardiovascular diseases, diabetes, or renal diseases.In this national cohort study, preadmission calcium channel blocker therapy before sepsis development was associated with a 6% reduction in mortality when compared with patients who have never received calcium channel blockers.