BACKGROUND Clinically, hepatectomy is a clean procedure performed without routine antimicrobial prophylaxis, regardless of the extent of liver loss. Translocation of endotoxin has been recognized as a fatal complication leading to liver failure. After extended hepatectomy, the portal hypertension, mucosal damage, intrahepatic bile acid retention, inhibited enterokinesia, and so forth are likely to contribute to enhanced endotoxin absorption. The effect of selective bowel decontamination (SBD) on the prognosis of hepatectomy were investigated. METHODS We adopted rat models of partial hepatectomy (70%, PHx) and subtotal hepatectomy (90%, SHx), gentamicin or saline of the same amount was administrated preoperatively. Liver damage makers, portal and systemic lipopolysaccharide, mucosal damage, signaling pathways, liver regeneration, and bile canalicular networks reconstruction were investigated. RESULTS We found that SHx but not PHx resulted in significantly enhanced portal and systemic endotoxin. Inhibition of gastrointestinal gram-negative bacteria by gentamicin significantly reduced lipopolysaccharide levels and improved survival after SHx (56% with gentamicin, 24% with saline, P < 0.05). We also found SBD with gentamicin protected intestinal mucosa barrier, alleviated liver parenchymal damage, and promoted liver regeneration and bile canalicular networks reconstruction after extended liver resection. CONCLUSIONS We conclude that SBD is beneficial and necessary for extended hepatectomy.