Cases of partial seroreversion have been reported in hemodialyzed or immunodepressed patients, but spontaneous clearance of viremia associated with a disappearance of specific antibodies or clearance while receiving therapy has not been precisely documented in immunocompetent hepatitis C virus (HCV)-infected persons. A longitudinal study of markers of HCV infection in a cohort of 178 multitransfused patients followed over an 8-year period was done to establish well-documented cases of partial or full seroreversion. Thirty (16.8%) of 178 patients were HCV-infected; among them, 5 had partial or full seroreversion. Seroreversion to an anti-HCV-negative state is characterized by a quantitative decrease in antibody. A seroreversion may be observed in three circumstances: spontaneously, induced by therapy, and in conjunction with human immunodeficiency virus infection. Long-term follow-up of seroreverters will establish whether they have definitively eradicated HCV from their systems.