Hepatitis C virus (HCV) is transmitted by percutaneous or permucosal exposure to infectious blood or blood-derived body fluids. Based on the results of cohort and acute case control studies, risk factors associated with acquiring HCV infection in the United States have included transfusion of blood and blood products and transplantation of solid organs from infected donors, injecting drug use, occupational exposure to blood (primarily contaminated needle sticks), birth to an infected mother, sex with an infected partner, and multiple heterosexual partners. Nosocomial and iatrogenic transmission of HCV primarily are recognized in the context of outbreaks, and primarily have resulted from unsafe injection practices. Transmission from HCV-infected health care workers to patients is rare. Transfusions and transplants have been virtually eliminated as sources for transmission, and most (68%) newly acquired cases of hepatitis C are related to injecting drug use. The primary prevention of illegal drug injecting will eliminate the greatest risk factor for HCV infection in the United States. Other prevention strategies that need to be widely implemented include risk reduction counseling and services and review and improvement of infection control practices in all types of health care settings. Testing for HCV infection should be routinely performed for persons at high risk for infection or who require postexposure management. There are no recommendations for routine restriction of professional activities for HCV-infected health care workers, and persons should not be excluded from work, school, play, and child care or other settings on the basis of their HCV infection status.