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Mounting evidence has shown that critically ill patients are commonly thiamine deficient. We sought to test the hypothesis that critically ill patients with septic shock exposed to thiamine would demonstrate improved lactate clearance and more favorable clinical outcomes compared with those not receiving thiamine.Retrospective, single-center, matched cohort study.Tertiary care academic medical center.Adult patients admitted with an International Classification of Diseases, 9th Edition, or International Classification of Diseases, 10th Edition, diagnosis code of septic shock to either the medicine or surgery ICU.None.Patients who received IV thiamine supplementation within 24 hours of hospital admission were identified and compared with a matched cohort of patients not receiving thiamine. The primary objective was to determine if thiamine administration was associated with a reduced time to lactate clearance in septic shock. Secondary outcomes included 28-day mortality, acute kidney injury, and need for renal replacement therapy, and vasopressor and mechanical ventilation-free days. Two-thousand two-hundred seventy-two patients were screened, of whom 1,049 were eligible. The study consisted of 123 thiamine-treated patients matched with 246 patients who did not receive thiamine. Based on the Fine-Gray survival model, treatment with thiamine was associated with an improved likelihood of lactate clearance (subdistribution hazard ratio, 1.307; 95% CI, 1.002–1.704). Thiamine administration was also associated with a reduction in 28-day mortality (hazard ratio, 0.666; 95% CI, 0.490–0.905). There were no differences in any secondary outcomes.Thiamine administration within 24 hours of admission in patients presenting with septic shock was associated with improved lactate clearance and a reduction in 28-day mortality compared with matched controls.