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To investigate the concentrations of mononuclear cell-associated ceramide and serum tumor necrosis factor-α (TNF-α) in patients with sepsis and to assess their predictive value for the development of multiple organ dysfunction syndrome (MODS).Prospective, cohort study.Intensive care unit and two research laboratories at a university hospital.Twenty-three adult patients admitted to an intensive care unit meeting the criteria for diagnosis of sepsis.Blood samples were collected at the time when diagnosis of sepsis was made.Mononuclear cell-associated ceramide and serum TNF-α were significantly elevated in the samples from the septic patients compared with the control individuals (318.01 ± 270.15 pmol/106 cells vs. 99.90 ± 52.75 pmol/106 cells; p < .001, and 28.52 ± 18.77 pg/mL vs. 10.43 ± 3.37 pg/mL; p < .0001, respectively), and a direct correlation linked ceramide and TNF-α concentrations (r2 = .90, p < .00001). In the septic patients who went on to develop MODS, ceramide and TNF-α were significantly higher compared with the no MODS patients (489.22 ± 264.93 pmol/106 cells vs. 131.23 ± 99.02 pmol/106 cells; p < .0001, and 40.96 ± 18 pg/mL vs. 14.95 ± 5.60 pg/mL; p < .001, respectively). The receiver operating characteristic curves demonstrated that both TNF-α and ceramide were prognostic of MODS, but ceramide concentrations were more efficient predictors.These observations suggest that mononuclear cells of peripheral blood from patients with sepsis are committed to undergo apoptosis, because there is evidence that ceramide acts as an endogenous mediator of apoptosis. The strong correlation we found between cell-associated ceramide and serum TNF-α supports the hypothesis that this cytokine plays an important role in activating the sphingomyelin pathway and ceramide generation in patients with sepsis. In addition, this study provides evidence that consistent concentrations of mononuclear cell-associated ceramide may predict progression toward MODS in septic patients.