The actions of zymosan on hepatic microcirculation and on the cell membrane permeability were investigated using the multiple-indicator dilution technique. The experimental system was the perfused rat liver. [(3)H]Water, [(3)H]sucrose and [(14)C]urea or [(14)C]bicarbonate were simultaneously injected into the portal vein. Mean transit times, distribution spaces, variances, linear superpositions and transfer coefficients across the plasma membrane were calculated. Zymosan had no net effect on the great vessels space but increased the extracellular sucrose space and decreased the aqueous cell space. Zymosan impaired the flow-limited distribution and increased the normalized variances of all tracers. The increase in the portal pressure caused by zymosan results most probably from a constriction just after or at the exit of the sinusoids. Impairment of the flow-limited distribution of tracers in the sinusoidal bed indicates that zymosan induces the formation of permeability barriers, which could make the access of the solutes to transporters or enzymes located on the outer surface of the plasma membrane difficult.