Acute infection with hepatitis C virus (HCV) is a frequent but underrecognized problem among substance users, because it produces few symptoms. Despite this fact, a good deal has been learned recently from studies of cohorts of persons with acute HCV infection. Intensive study of these cohorts has suggested that there is a higher frequency of spontaneous clearance among persons with symptomatic infection and persons with vigorous adaptive immune responses. Similarly, polymorphisms for genes involved in innate immunity also appear to influence the outcome of acute HCV infection. Data on injection drug users with repeated exposures to HCV reveal the presence of partially protective immunity, which suggests that vaccine-based approaches may be feasible. Finally, antiviral therapy with interferon-based regimens for acute HCV infection produces significantly higher sustained virological responses than observed for chronic infection. Further work is needed to develop more-accurate assays for acute HCV infection, to define host and viral factors that predict outcome and to define the optimal duration and regimen of therapy.