The response of hepatic macrophages and the effects of platelet-activating factor (PAF) in perfused liver were studied during production of experimental cirrhosis induced by thioacetamide (TAA) in female Sprague-Dawley rats. Within 4 weeks of TAA administration (300 mg/L drinking water), an increase in hepatic macrophage population and enlargement in cell size preceded the alterations characteristic of cirrhosis. During 12 weeks of TAA administration, the changes in hepatic macrophages were maintained and cirrhosis of the micronodular type developed with a marked increase in hydroxyproline content. Although TAA treatment for 4 weeks had no effect on oxygen consumption or hepatic portal pressure in the perfused liver, the increment in hepatic portal pressure and decrement in oxygen consumption induced by PAF in TAA-treated rats were double those in control rats. The amounts of prostaglandin D2 (PGD2) and thromboxane B2 (TxB2) in perfusate induced by PAF were seven- and fivefold greater, respectively, in TAA-treated rats than in control rats. Zymosan mimicked the effects of PAF. These results are consistent with the hypothesis that hepatic macrophages and PAF play important roles in the development of cirrhosis induced by TAA.