Serial alpha-fetoprotein (AFP) levels, measured from 32 to more than 500 days in 40 patients with hepatocellular carcinoma, accurately reflected a response to chemotherapy or surgery. In patients who failed to respond to chemotherapy and in those who relapsed after initially successful chemotherapy or surgery, AFP concentration rose exponentially with time. The rate of rise as characterized by the doubling time ranged from 6.5 to 112 days (mean, 41 days), correlated positively with survival time, and proved a useful guide to prognosis. Falls in AFP concentrations were associated with a decrease in tumor mass, although the achievement of a normal level did not necessarily imply complete tumor clearance as shown in 2 patients who had been treated by transplantation and in whom the tumor recurred. Data based on AFP concentrations at the time of clinical presentation and AFP doubling time suggest that increasing concentrations of AFP detectable by radioimmunoassay may be present up to 18 months before appearance of symptoms. In this way screening of high-risk groups, i.e., men with cirrhosis, could lead to significantly earlier diagnosis.