Liver mass is regulated in precise proportion to body mass in healthy animals, and this ratio (liver:body weight) is specifically restored by regeneration following acute injury. Despite extensive analysis of the molecular mechanisms that regulate hepatic regeneration, the specific signals that initiate and terminate the regenerative response and those that determine the ideal liver:body mass ratio have not been elucidated. Previous analyses have suggested the mechanisms involved in such regulation are likely to include signals derived from the bowel via the portal circulation. Therefore, in the studies reported here we investigated the effect of partial small bowel resection on regulation of liver mass in a murine surgical model. Methods: Two month old, male C57BL/6J wildtype mice were subjected to partial small bowel resection or sham surgery (transection without resection) followed by primary reanastamosis, as we have previously described. These animals were allowed to recover, after which they were sacrificed at serial time points for determination of liver:body mass ratio and analysis of liver tissue. Results: In mice subjected to removal of ~50% of proximal small intestine, liver:body weight ratio was decreased 10% at 48 hrs and 20% at 72 hrs after surgery compared to sham operated animals (p<0.01). Similar results were seen in animals in which a comparable amount of distal small bowel was resected. Functional liver mass was also reduced based on analyses of total hepatic protein (reduced 30% versus sham, p<0.01) and total hepatic alanine transaminase (ALT) activity (reduced 50% versus sham, p<0.001) in the remnant organ 72 hours after small bowel resection. Morphometric analysis also showed reduction in hepatocellular size in animals subjected to small bowel resection (reduced 15% versus sham, p<0.02). Protein immunoblot analysis demonstrated increased expression of LC3-II, a marker of autophagic induction, and an increase in the ratio of Bax:Bcl-2 protein expression, an indicator of activation of pro-apoptotic signaling, in the livers of bowel-resected animals (p<0.01 versus sham). Summary and Conclusions: The studies reported here show that total and functional liver mass is reduced following partial small bowel resection, and this reduction is associated with induction of pro-autophagic and pro-apoptotic signaling events. These data have important implications with respect to the pathogenesis and management of liver disease seen in the setting of partial small bowel resection, for example in neonates who undergo substantial small bowel resection for necrotizing enterocolitis.