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Background: Recent studies suggest that hydrocortisone, Vitamin C, and thiamine alone or in combination may improve the clinical outcomes of patients with septic shock. The aim of this study is the effects of this combination therapy on clinical outcome and sepsis biomarkers in patients with septic shock. Materials and Methods: Fifty-eight consecutive patients suffering septic shock were randomly assigned into two groups receiving the combination therapy of hydrocortisone (50 mg/6 h, intravenously), Vitamin C (1.5 g/6 h in 100 ml normal saline or DW5%, intravenously), and thiamine (200 mg/12 h in 50 ml normal saline or DW5%, intravenously) or placebo for up to 4 days. Results: The decline in procalcitonin, lactate, and leukocyte count 72 h after the initiation of treatment was significantly greater in the intervention as compared to the control group. The intervention group has a significantly lower sequential organ failure assessment score 72 h after treatment (P < 0.001). The mean duration of vasopressor dependency was shorter in the intervention group (P = 0.039). In-hospital death occurred in 10.3% of the patients who received combination therapy and 37.9% in the control group (P = 0.014). Conclusion: The administration of the triple combination of hydrocortisone, thiamine, and Vitamin C appeared to be effective in improving the clinical outcomes of patients with septic shock and of reducing vasopressor requirements with a significant increase in the rate of improvement of sepsis biomarkers. [ABSTRACT FROM AUTHOR]