We assessed the impact, over a 28-d period, of therapy with the tumor necrosis factor (TNF) neutralizing receptor fusion protein (p55-IgG) on the incidence of end-organ failures in patients with severe sepsis or early septic shock in a subgroup of 165 patients recruited into a randomized, multicenter clinical trial to receive placebo (n = 78) or a single infusion of p55-IgG, 0.083 mg/kg (n = 87). At study entry, distribution of organ dysfunctions and other baseline characteristics were similar for the two study groups. Treatment with p55-IgG was associated with a trend toward reduced 28-d mortality (p = 0.07), a decreased incidence of new organ dysfunctions (relative risk [RR], 0.57; 95% confidence interval [95% CI] 0.29 to 1.10, p = 0.10), and a decreased overall incidence-density of organ failures (RR 0.65; 95% CI 0.60 to 0.71, p = 0.0001). Patients treated with p55-IgG had more organ failure-free days after study entry than those who received placebo. Average intensive care unit (ICU) stay was 2.6 d shorter (95% CI 0.2 to 5.0) for patients who received p55-IgG than for those who received placebo. For those patients who survived, this difference was 4.1 d (95% CI 1.6 to 6.6). Duration of ventilatory support was 3.2 d shorter (95% CI 0.1 to 6.3) among 28-d survivors who received p55-IgG, compared with placebo. In conclusion, in the population of septic patients studied, treatment with p55-IgG was associated with a trend toward shorter need for mechanical ventilatory support, a decreased length of stay (LOS), and a decreased incidence and duration of organ failure.