Measurement of hepatic sinusoidal permeability of oxygen and other substrates may help elucidate the mechanisms responsible for impaired liver function in cirrhosis. However studies of sinusoidal oxygen permeability in normal liver and various disease states have been limited due to the considerable technical difficulties involved in the use of standard techniques. We have developed a new method for measuring sinusoidal oxygen permeability in the isolated perfused rat liver that overcomes the difficulties of previous methods by using [(15)O]O(2) and an in-line fluid monitor. This method uses data obtained from impulse response curves of radiolabelled red cells, albumin and oxygen that are fitted mathematically using the axial dispersion model to yield rate constants that describe oxygen transit through the liver. We have demonstrated the utility and reproducibility of this method by comparing multiple injections and permeability determinations in the same preparation. This approach could be used in isolated perfused organs to study oxygen permeability in a range of disease states.