Sepsis is the major cause of mortality on intensive care units (ICU) with ~36,000 deaths annually in the UK. Sepsis is a systemic, dysregulated activation of the innate immune system in response to an infection characterised by excessive inflammatory mediator production and oxidative stress. Mitochondrial dysfunction is implicated in sepsis-­‐induced organ dysfunction and death. Zinc is an essential micronutrient with a multitude of biological functions, including anti-­‐inflammatory and antioxidant properties. A relationship has been established between zinc deficiency and severity of sepsis, in which zinc deficiency negatively influences the processes of sepsis leading to organ damage and ultimately death. This study investigated the effect of zinc on sepsis-­‐related mechanisms to evaluate its importance for sepsis pathophysiology. The relationship between zinc levels and sepsis-­‐related molecular mechanisms were investigated in an endothelial cell culture model of sepsis and in blood samples obtained from patients on ICU with and without sepsis. The in vitro study showed no evidence of zinc as an antioxidant or anti-­‐inflammatory agent in endothelial cells exposed to lipopolysaccharide and peptidoglycan, however mitochondrial baseline function was increased in a zinc concentration-­‐dependent manner. Plasma zinc levels were far below normal in all patients and patients with sepsis had lower levels compared to non-­‐infected patients, possibly because they were overall more severely ill. No clear correlations could be established between plasma zinc and markers of inflammation, oxidative stress or disease severity. The lack of anti-inflammatory and antioxidant properties of zinc in the endothelial sepsis model, and the lack of clear correlations between zinc and markers of disease severity, inflammation and oxidative stress in the clinical study, challenges the concept of the importance of zinc in the pathophysiology of sepsis. The prolonged reduction of plasma zinc in all ICU patients prompts to consideration of zinc supplementation to replenish plasma levels and assure sufficient availability to maintain tissue functions.