In a 4-year follow-up study, patients with acute sporadic non-A, non-B (NANB) hepatitis were evaluated to determine the etiology and natural history of the disease. Acute hepatitis C virus (HCV) was detected in 13 of 43 (30%) of patients, anti–hepatitis E virus (HEV) IgG in 5 (12%), and 25 (58%) were considered non–A-E. The HCV RNA was detected in all HCV patients but none of the non–A-E cases. The initial clinical and biochemical presentation of the HCV and non–A-E cases was quite similar, although 2 of the non–A-E patients had severe disease. The 5 patients who were found to be anti-HEV IgG–reactive recovered within 6 months of follow-up. Of the 13 HCV cases, alanine transaminase (ALT) levels returned to normal in 7 (53.8%), while 6 (46.2%) continued to show abnormal ALT after 6 months of follow-up. However, 9 (69.2%) of them remained HCV-RNA–positive, denoting virological/biochemical dissociation. Long-term follow-up showed a reappearance of HCV RNA in 2 of the 4 patients who were in virological remission performing 84% of chronicity rate. Acute non–A-E hepatitis patients were less likely to evolve toward chronicity, as compared with acute HCV cases (16% vs. 84%; P = .0001). Only 4 (16%) of the non–A-E patients were hepatitis G virus (HGV)-RNA–positive. Concerning risk factors for acquiring parenterally transmitted viruses, tattooing was the only one that could be associated with HCV transmission (P = .002). No risk factors could be identified for putative non–A-E virus transmission. Liver biopsies performed for chronic HCV patients showed a variable degree of inflammation, while the non–A-E patients presented less severe histological disease.