A novel DNA virus, TT-virus (TTV), has been reported in patients with non-A-G posttransfusion hepatitis in Japan. We sought to determine whether TTV infection occurs in North American blood donors and to further determine the prevalence of TTV infection in several groups of patients with liver disease, including patients with cryptogenic cirrhosis and idiopathic fulminant hepatic failure. TTV infection was sought by detection of TTV DNA in serum by polymerase chain reaction (PCR) using primers generated from a conserved region of the TTV genome. Blood donors, patients with cryptogenic cirrhosis, idiopathic fulminant hepatic failure, and patients with other forms of advanced liver disease with and without a history of parenteral exposures were studied. TTV infection was present in 1% (1 of 100) of blood donors, 15% (5 of 33) of patients with cryptogenic cirrhosis, 27% (3 of 11) of patients with idiopathic fulminant hepatic failure, 18% (2 of 11) of patients with a history of exposure to blood products, and 4% (1 of 25) of patients without parenteral risk factors. For all patients tested, a history of prior exposure to blood products was associated with an increased risk of TTV infection (relative risk, 4.5; 90% confidence intervals, 0.6-43.9). We conclude that TTV infection is present among North American blood donors and is common in patients with liver disease, including cryptogenic cirrhosis and fulminant hepatic failure. Further studies are required to determine the role of TTV in the pathogenicity of acute and/or chronic liver disease.