Pegylated interferon ␣ (PEG IFN-␣) improves sustained virological response rates in chronic hepatitis C, but neither its role in acute hepatitis C nor the biologic basis for its action has been defined. This prospective study assessed the efficacy of PEG IFN-␣ treatment in acute hepatitis C in relation to the kinetics of hepatitis C virus (HCV)-specific CD4 ؉ T cell responses during therapy and follow-up. Forty subjects with proven acute hepatitis C who received either PEG IFN-␣ plus ribavirin (n ؍ 20) or PEG IFN-␣ monotherapy (n ؍ 20) for 24 weeks in addition to 14 untreated subjects with acute hepatitis C were prospectively followed. Serum HCV RNA, HCV-specific CD4 ؉ T cell responses, and cytokine production were measured before and during therapy and at follow-up and correlated to the outcome. The sustained virological response rate was 85% with PEG IFN-␣/ribavirin combination and 80% with PEG IFN-␣ monotherapy. Five untreated subjects had spontaneous recovery. The frequency, magnitude, and breadth of HCV-specific CD4 ؉ T helper 1 responses were significantly higher in treated subjects compared with untreated subjects with self-limited disease or subjects with chronic evolution. The CD4 ؉ T cell responses were maintained in subjects with sustained virological responses and self-limited disease but fluctuated in those who developed chronic infection. In conclusion, PEG IFN-␣ therapy in acute hepatitis induces high rates of sustained virological response and prevents choronicity, probably through efficient early stimulation of multispecific HCV-specific CD4 ؉ T helper 1 responses. (HEPATOLOGY 2004;39:1721-1731.