Because there is no effective neutralizing antibody or vaccine for preventing hepatitis C virus (HCV) transmission, HCV can be transmitted to health care workers through accidental needlesticks. Recently, two of our health care workers acquired HCV infection through needlestick accidents and developed acute hepatitis C. The route of transmission was confirmed by molecular evolutionary analysis with use of the E2 region of the HCV genome. After the clinical onset of acute hepatitis, the health care workers were treated with interferon (IFN) (total dose, approximately 300 megaunits). Neither individual developed chronic hepatitis. This finding raises the possibility that treatment with low-dose IFN following an accidental needlestick may be beneficial, even when it is started after the clinical onset of hepatitis.