Hepatic portal venous infusion of nitric oxide synthase (NOS) inhibitors causes muscle insulin resistance, but the effects on hepatic glucose disposition are unknown. Conscious dogs underwent a hyperinsulinemic (4-fold basal), hyperglycemic (hepatic glucose load 2-fold basal) clamp, with assessment of liver metabolism by arteriovenous difference methods. After 90 min (P1), dogs were divided into two groups: Control (n=8), receiving intraportal saline infusion, and LN (n=11), receiving L-NAME, a NOS inhibitor, intraportally at 0.3 mg·kg^-1·min^-1 for 90 min (P2). During the final 60 min (P3), L-NAME was discontinued, and five LN dogs received the NO donor SIN-1 intraportally at 6 µg·kg^-1·min^-1 while six received saline (LN/SIN-1 and LN/SAL, respectively). Net hepatic fractional extraction of glucose (NHFE) in Control was 0.034±0.016, 0.039±0.015, and 0.056±0.019 in P1, P2, and P3, respectively. NHFE in LN was 0.045±0.009 and 0.111±0.007 during P1 and P2 (P<0.05 vs Control during P2), and 0.087±0.009 and 0.122±0.016 (P<0.05) in P3 in LN/SIN-1 and LN/SAL, respectively. During P2, arterial glucose was 204±5 vs 138±11 mg/dl (P<0.05) in LN vs Control. Therefore another group (LNlow, n=4) was studied as was LN/SAL, except that the arterial glucose was clamped at the same concentrations as in Control, and L-NAME infusion was reduced 75%. NHFE in LNlow was 0.052±0.008, 0.093±0.023, and 0.122±0.021 in P1-P3, respectively (P<0.05 vs Control in P2-P3) and glycogen synthesis was enhanced 38% (P=0.16). Thus, NOS inhibition enhanced NHFE, an effect partially reversed by SIN-1.