We hypothesized that severely injured obese patients would display increased concentrations of proinflammatory cytokines when compared with patients of normal body mass index (BMI) and that this would be associated with multiple organ failure (MOF). This was a retrospective review of prospectively collected data in the “Inflammation and the Host Response to Injury” trauma-related database. Data were collected prospectively from US level I trauma centers. The subjects were severely injured adult blunt trauma patients. Cytokine concentrations obtained within 12 h of injury and on days 1 and 4 were compared between subjects on the basis of BMI (normal, 18.5–24.9 kg/m2, and obese, ≥30 kg/m2). Demographic measures, injury severity, cytokine concentrations, and outcome measures were compared between groups. Seventy-four adult blunt trauma victims were evaluated. Relative to patients of normal BMI (n = 34), obese patients (n = 40) demonstrated an overall depressed cytokine response to severe injury, with significantly lower concentrations of several cytokines. Obese patients showed greater incidences of nosocomial infection (60 vs. 45%, not statistically significant) and MOF (63% vs. 44%, not statistically significant) and a later onset of maximum MOF score (5 vs. 3 days, P < 0.04) when compared with those of normal BMI. Despite prior reports suggesting a proinflammatory cytokine profile in obese individuals, obese patients sustaining severe injury show a depressed early cytokine response when compared with patients of normal BMI. This may confer increased susceptibility to nosocomial infection and later MOF. Further study of immune dysfunction in the postinjury obese patient should assess the possibility of early immune suppression.