One-hundred and thirty-three consecutive ascitic patients hospitalized in our Liver Unit were prospectively investigated, to define the accuracy of ascitic fluid analysis in identifying malignancy. Patients with extrahepatic cancer and peritoneal carcinomatosis were characterized by positive cytology and higher ascitic levels of fibronectin, lactic dehydrogenase, carcinoembryonic antigen, and total protein than both patients with uncomplicated cirrhosis and patients with cirrhosis and liver cancer. Ascitic cytology, fibronectin, and lactic dehydrogenase (LDH) were the most sensitive and specific markers of extrahepatic malignancy. In contrast, none of these markers was useful in identifying patients with primary liver cancer complicating cirrhosis. For them, the only alteration of the ascitic fluid was an elevated alpha-fetoprotein concentration. The sensitivity, specificity, and accuracy of ascitic alpha-fetoprotein for detecting liver cancer were 87%, 95%, and 94%, respectively. Combining cytology with the determinations of fibronectin (or LDH) and alpha-fetoprotein in ascitic fluid satisfactorily differentiated 28 of 32 cases of malignancy-related ascites, with very low incidence of false-positives (4-6%). Therefore, in view of the frequent difficulties in detecting liver cancer as a complication of cirrhosis in patients with ascites, it is advisable to determine all these three markers in the same ascitic sample.