Approximately 85% of persons with acute hepatitis C develop chronic hepatitis as determined by persistently abnormal serum enzymes and/or viremia (hepatitis C virus [HCV] RNA). Both the acute and chronic illnesses are predominantly asymptomatic. For this reason and because the chronic illness runs an extremely protracted course, it has been difficult to accurately define the frequency and rate of progression to symptomatic or end-stage liver disease, specifically cirrhosis and hepatocellular carcinoma (HCC). Three evaluation strategies have been used. The first, prospective studies beginning from disease onset, have identified over 8 to 14 year follow-up periods that morbidity (symptoms, cirrhosis) and mortality (hepatic failure, HCC) are modest in frequency. The second, prospective studies of subjects with already established chronic liver disease, have demonstrated high rates of development of cirrhosis, HCC, and mortality over relatively short follow-up periods. The third, retrospective/prospective (nonconcurrent prospective) studies, has consisted of follow-up of recipients of HCV-contaminated immunoglobulin and of transfusion recipients from five enzyme-monitored transfusion studies of the early 1970s. The former study identified no mortality, trivial morbidity, and minimal cirrhosis 17 years after infection. The latter, involving hepatitis cases and matched nonhepatitis controls studied over a 20-year period, demonstrated no increase in all-cause but a slight increase in liver-related mortality. Clinically evident chronic liver disease was noted to be minimal among those in follow-up with biochemically defined chronic hepatitis whose biopsy specimens showed no cirrhosis, but common among those with histologically detected cirrhosis. More than 90% of subjects with an original diagnosis of transfusion-related hepatitis C have remained positive for antibody to HCV (anti-HCV), most with persistent viremia. Two thirds of the anti-HCV-positive individuals have biochemically defined chronic hepatitis, whereas one third have persistently normal enzymes. Taken together, available data suggest that in the first two decades after infection, mortality and morbidity are modest in frequency. Both can be expected to increase as the disease advances to the third and fourth decades after acute infection, especially among those with established cirrhosis. The outcome among those with chronic hepatitis but without cirrhosis remains to be determined.