BACKGROUND Violence-related injuries, including suicide, adversely affect the health and welfare of all Americans through premature death, disability, medical costs, and lost productivity. Estimating the magnitude of the economic burden of violence is critical for understanding the potential amount of resources that can be saved if cost-effective violence prevention efforts can be broadly applied. From 2003 to 2005, the lifetime medical costs and productivity losses associated with medically treated injuries due to interpersonal and self-directed violence occurring in the United States in 2000 were assessed. METHODS Several nationally representative data sets were combined to estimate the incidence of fatal and nonfatal injuries due to violence. Unit medical and productivity costs were computed and then multiplied by corresponding incidence estimates to yield total lifetime costs of violence-related injuries occurring in 2000. RESULTS The total costs associated with nonfatal injuries and deaths due to violence in 2000 were more than $64.8 [corrected] billion. Most of this cost ($64.4 billion or 92%) was due to lost productivity. However, an estimated $5.6 billion was spent on medical care for the more than 2.5 million injuries due to interpersonal and self-directed violence. CONCLUSIONS The burden estimates reported here provide evidence of the large health and economic burden of violence-related injuries in the U.S. But the true burden is likely far greater and the need for more research on violence surveillance and prevention are discussed.