This study investigates the determinants of viral clearance and persistence during acute hepatitis C virus (HCV) infection in five healthcare workers exposed to HCV-positive blood. Four of the subjects developed chronic HCV infection, while one cleared the virus. Viremia was first detectable within 1–2 weeks of infection, before the appearance of virus-specific T cells. The subject who cleared the virus experienced a prolonged acute hepatitis phase, followed by a strong CD4⁺ T cell response and a rapid 100,000-fold decrease in viremia. In contrast, two subjects who failed to produce a significant T cell response and two others who initially had strong CD4⁺ responses that waned developed chronic infection. Viremia was highest at the peak of acute hepatitis and decreased as the disease improved. The results suggest that the vigor and quality of the antiviral T cell response determine the outcome of acute HCV infection, while the virus's ability to outpace the T cell response may contribute to its persistence. The onset of hepatitis coincides with the onset of the CD8⁺ T cell response, and disease pathogenesis and viral clearance are mediated by different CD8⁺ T cell populations. The study provides the first insight into the host-virus relationship during the incubation phase of acute HCV infection and the virological and immunological characteristics of clinically asymptomatic acute HCV infection. The findings highlight the importance of CD4⁺ and CD8⁺ T cell responses in controlling HCV, and suggest that noncytolytic mechanisms may also play a role in viral clearance. The study also indicates that different pathways may lead to viral persistence in asymptomatic and symptomatic acute HCV infection. The results emphasize the critical role of the T cell response in the pathogenesis of liver disease and the control of HCV during the incubation phase of infection.This study investigates the determinants of viral clearance and persistence during acute hepatitis C virus (HCV) infection in five healthcare workers exposed to HCV-positive blood. Four of the subjects developed chronic HCV infection, while one cleared the virus. Viremia was first detectable within 1–2 weeks of infection, before the appearance of virus-specific T cells. The subject who cleared the virus experienced a prolonged acute hepatitis phase, followed by a strong CD4⁺ T cell response and a rapid 100,000-fold decrease in viremia. In contrast, two subjects who failed to produce a significant T cell response and two others who initially had strong CD4⁺ responses that waned developed chronic infection. Viremia was highest at the peak of acute hepatitis and decreased as the disease improved. The results suggest that the vigor and quality of the antiviral T cell response determine the outcome of acute HCV infection, while the virus's ability to outpace the T cell response may contribute to its persistence. The onset of hepatitis coincides with the onset of the CD8⁺ T cell response, and disease pathogenesis and viral clearance are mediated by different CD8⁺ T cell populations. The study provides the first insight into the host-virus relationship during the incubation phase of acute HCV infection and the virological and immunological characteristics of clinically asymptomatic acute HCV infection. The findings highlight the importance of CD4⁺ and CD8⁺ T cell responses in controlling HCV, and suggest that noncytolytic mechanisms may also play a role in viral clearance. The study also indicates that different pathways may lead to viral persistence in asymptomatic and symptomatic acute HCV infection. The results emphasize the critical role of the T cell response in the pathogenesis of liver disease and the control of HCV during the incubation phase of infection.