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IntroductionSepsis is a leading cause of morbidity and mortality in intensive care units, characterized by a dysregulated host response to infection. Recent evidence suggests fluoxetine, a selective serotonin reuptake inhibitor, may exert immunometabolic effects beneficial in sepsis. The aim of this study is to evaluate the effect of fluoxetine on vasopressor duration, organ dysfunction, inflammatory markers, and mortality in adult patients with severe sepsis.Materials and methodsIn this single-center, randomized, double-blind, placebo-controlled trial conducted at Ain Shams University Hospitals (December 2024–June 2025), 46 patients with severe sepsis were randomized 1:1 to receive either fluoxetine (40 mg/day) or placebo in addition to standard sepsis care. The primary outcome was vasopressor duration. Secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, inflammatory biomarkers (CRP, TNF-α, IL-1, procalcitonin), lactate levels, ICU length of stay, and 28-day mortality.ResultsFluoxetine significantly reduced vasopressor duration (6.2 ± 0.4 vs. 7.9 ± 0.8 days; p ConclusionsFluoxetine as adjunctive therapy in severe sepsis may reduce vasopressor dependence, attenuate inflammation, and shorten ICU stay without increasing adverse effects. Its mortality benefit remains uncertain and warrants further investigation.