Pentobarbital therapy has been associated with decreased urinary nitrogen excretion and resting energy expenditure in stressed patients. The metabolic effects of pentobarbital in sepsis were investigated in 29 well-nourished rats who underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 20 mg/kg/day of pentobarbital combined with parenteral nutrition (n = 13) or parenteral nutrition alone (n = 16). Both groups received isocaloric, isonitrogenous parenteral nutrition postoperatively for 24 hr. Mean nitrogen balance (+/- SEM) was better in the pentobarbital group (+169 +/- 76 mg/kg/day vs -190 +/- 66 mg/kg/day, p less than 0.01). No significant differences between the pentobarbital and control groups were noted for urinary 3-methylhistidine excretion (9 +/- 0.7 micrograms/kg/day vs 11 +/- 0.6 micrograms/kg/day, respectively) or 24 hr survival (77% vs 69%, respectively). Pentobarbital improves nitrogen retention without decreasing urinary 3-methylhistidine excretion in septic rats.