The aim of this study was to investigate the effects of caffeic acid phenethyl ester (CAPE) on inflammatory and related histopathological changes in the lung and liver in experimental hepatopulmonary syndrome (HPS) model. Forty Sprague Dawley rats were used in this study. The animals were divided into four groups of ten rats each. Group 1 and 2 was subjected the common bile duct (CBD) but not ligated, Group 3; (cirrhosis + saline): the CBD was ligated and was given intraperitoneal saline infusion treatment during 5 weeks. Group 4; (cirrhosis + CAPE): the CBD was ligated and was given intraperitoneal CAPE infusion treatment during 5 weeks. A 5-week waiting period was observed for the development of cirrhosis and the rats' lungs and liver were taken for histopathological examination. The induction of HPS resulted in a significant increase in serum bilurubin, AST, ALT, and NO levels, and decrease PO2 and O-2 saturation. The use of CAPE significant decrease these parameters. Histopathological examination revealed less congestion, portal inflammation, and nodular formations of the liver, and less congestion, emphysematous and inflammatory changes and smallest perialviolar vascular diameters, in the lung in the cirrhosis + CAPE groups than in the other groups. CAPE treatment may be a potential approach for the treatment of hepatopulmonary syndrome in the future.