TT virus (TTV) has been proposed as the causative agent of non-A to E hepatitis. We studied the association between TTV viremia and biochemical evidence of hepatitis in blood donors and prospectively-followed patients. TTV was found in 7.5% of 402 donors and in 11.0% of 347 patients before transfusion. The rate of new TTV infections was 4.7% in 127 nontransfused, and 26.4% in 182 transfused patients (P F .0001). The risk of infection increased with the number of units transfused (P F .0001). The rate of new TTV infections in 13 patients with non-A to E hepatitis (23.2%) was almost identical to the rate in 124 patients who were transfused, but did not develop hepatitis (21.8%). Of 45 patients with acute hepatitis C, 40.0% were simultaneously infected with TTV. TTV did not worsen the biochemical severity (mean ALT: 537 in TTVุ; 550 in TTVุ) or persistence of hepatitis C. In non-A to E cases, the mean ALT was 182 in those TTV-positive and 302 in TTV-negatives. No consistent relationship between alanine transaminase level and TTV DNA level was observed in 4 patients with long-term, sequential samples. Of 21 viremic subjects, 67% cleared TTV within 5 years (38% in 1 year); 33% were viremic throughout follow-up extending to 22 years. We conclude that TTV is a very common, often persistent infection that is transmitted by transfusion and by undefined nosocomial routes. We found no association between TTV and non-A to E hepatitis and no effect of TTV on the severity or duration of coexistent hepatitis C. TTV may not be a primary hepatitis virus. (HEPATOLOGY 1999;30:283-288.