Introduction: Infants with short bowel syndrome (SBS) are at a high risk for infectious complications and liver failure. We hypothesized that SBS, independent of total parenteral nutrition, is a proinflammatory state that is magnified by sepsis. Methods: Sprague-Dawley rats were divided into 2 groups: sham laparotomy (SH, n = 10) or 75% small bowel resection (n = 10). After 14 days, each group underwent a second sham laparotomy (SH/SH and SBS/SH) or cecal ligation and puncture, followed 16 hours later by cecal excision and peritoneal washout (SH/sepsis and SBS/sepsis). Animals were killed 56 hours later. Results: The SBS rats had higher serum levels of interleukin (IL) 6 vs SH (355 ± 99 vs 104 ± 71 pg/mL, P < .05). Liver injury scores were higher in SBS/sepsis compared with SBS/SH animals (3.7 ± 0.7 vs 1.9 ± 0.3, P < .05). Hepatic messenger RNA levels of IL-6 (12.8-fold change [FC]) and tumor necrosis factor α (5.65 FC) were elevated in SBS vs SH rats; and IL-6 (114 FC), tumor necrosis factor α (3.87 FC), and Toll-like receptor 4 (7.65 FC) were increased in SBS/sepsis compared with SH/sepsis animals. Conclusion: Our results suggest that SBS, independent of total parenteral nutrition, is a proinflammatory state and that sepsis induces an exaggerated proinflammatory cytokine response that may play an important role in liver damage and may be mediated by Toll-like receptor 4. Crown Copyright © 2007.