Gut-derived norepinephrine (NE) has been shown to play a critical role in producing hepatocellular dysfunction in early sepsis, but it is not known whether ₂-adrenoceptor activation mediates this dysfunction. We infused normal male adult rats with NE, NE plus the specific ₂-adrenergic antagonist rauwolscine (RW), or vehicle (normal saline) for 2 h. Hepatocellular function was determined by in vivo indocyanine green (ICG) clearance. An isolated perfused liver preparation was also used to assess hepatocellular function by in vitro ICG clearance; NE alone or with RW was added to the perfusate. Rats were subjected to sepsis by cecal ligation and puncture (CLP). At 1 h after CLP, RW was infused for 15 min. At 5 h after CLP, we measured hepatocellular function and serum tumor necrosis factor- (TNF-) levels. Intraportal NE infusion in normal rats produced hepatocellular dysfunction, which was prevented by RW and NE infusion. This is confirmed by findings with the isolated perfused liver preparation. RW administration in early sepsis maintained hepatocellular function and downregulated TNF- production at 5 h after CLP. These results suggest that NE-induced hepatocellular dysfunction in early sepsis is mediated by ₂-adrenoceptor activation, which appears to upregulate TNF- production. Modulation of hepatic responsiveness to NE by ₂-adrenergic antagonists should provide a novel approach for maintaining cell and organ functions during sepsis.