Experiments were carried out to determine the accuracy and validity of estimations of hepatic blood flow from systemic clearances of ethanol during very low dose (8 μmol∙min−1∙kg−1) infusions of ethanol in anesthetized cats. Systemic clearances were compared with directly measured hepatic blood flow using a hepatic venous long-circuit technique. This technique allowed direct measurement and alteration of hepatic blood flow and collection of arterial, portal, and hepatic venous blood samples without depletion of the animal's blood volume. In 18 cats, Vmax for ethanol was 93 ± 7 μmol∙min−1 per 100 g liver or 21 ± 2 μmol∙min−1∙kg·body weight−1 and Km was 144 ± 19 μM in terms of logarithmic mean sinusoidal concentration. At the dose of 8 μmol∙min−1∙kg body weight−1 used for estimation of hepatic blood flow, extraction was 0.95 ± 0.07 (mean ± SD). Systemic clearance of ethanol overestimated directly measured hepatic blood flow by 15 ± 16%. Hepatic blood flow changes expressed as percentages of the control level were accurately estimated from systemic ethanol clearance (100 ± 10%). Since 73 ± 12% of the infused ethanol was eliminated by the liver and 83 ± 11% was eliminated by the splanchnic bed, an extrasplanchnic uptake of 17% accounted for the overestimation of hepatic blood flow. Estimation of hepatic blood flow from systemic clearances of ethanol during very low dose infusions may have advantages over other clearance methods. Its use in cats was illustrated in a separate series of experiments and it was shown that surgery significantly reduced hepatic blood flow. The method may merit trial for estimation of hepatic blood flow in humans.