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Objectives: To examine the effect of premorbid β-blocker exposure on mortality and organ dysfunction in sepsis.Design: Retrospective observational study.Setting: ICUs in Australia, the Czech Republic, and the United States.Patients: Total of 4,086 critical care patients above 18 years old with sepsis between January 2014 and December 2018.Intervention: Premorbid beta-blocker exposure.Measurements and Main Results: One thousand five hundred fifty-six patients (38%) with premorbid β-blocker exposure were identified. Overall ICU mortality rate was 15.1%. In adjusted models, premorbid β-blocker exposure was associated with decreased ICU (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97; p = 0.025) and hospital (adjusted odds ratio, 0.83; 95% CI, 0.71-0.99; p = 0.033) mortality. The risk reduction in ICU mortality of 16% was significant (hazard ratio, 0.84, 95% CI, 0.71-0.99; p = 0.037). In particular, exposure to noncardioselective β-blocker before septic episode was associated with decreased mortality. Sequential Organ Failure Assessment score analysis showed that premorbid β-blocker exposure had potential benefits in reducing respiratory and neurologic dysfunction.Conclusions: This study suggests that β-blocker exposure prior to sepsis, especially to noncardioselective β blockers, may be associated with better outcome. The findings suggest prospective evaluation of β-blocker use in the management of sepsis. [ABSTRACT FROM AUTHOR]