The rate of transmission and management of needlestick injuries from hepatitis C virus (HCV) patients to healthcare workers is still a matter of debate. We used a stringent protocol using monthly transaminase levels and polymerase chain reaction for HCV RNA to monitor 53 healthcare workers prospectively for up to 6 months following needle injuries from HCV-positive patients. Evidence of transmission of HCV was found in only 2 workers (4%) with mild asymptomatic infection, one of which resolved spontaneously. Based on our experience, we now use a less-intensive follow-up protocol. Further investigation is required to determine the most cost-effective method to monitor individuals who suffer a needlestick injury from an HCV-positive patient.