Urgent débridement of open fractures has been considered to be of paramount importance for the prevention of infection. The purpose of the present study was to evaluate the relationship between the timing of the initial treatment of open fractures and the development of subsequent infection as well as to assess contributing factors. Three hundred and fifteen patients with severe high-energy lower extremity injuries were evaluated at eight level-I trauma centers. Treatment included aggressive débridement, antibiotic administration, fracture stabilization, and timely soft-tissue coverage. The times from injury to admission and operative débridement as well as a wide range of other patient, injury, and treatment-related characteristics that have been postulated to affect the risk of infection within the first three months after injury were studied, and differences between groups were calculated. In addition, multivariate logistic regression models were used to control for the effects of potentially confounding patient, injury, and treatment-related variables. Eighty-four patients (27%) had development of an infection within the first three months after the injury. No significant differences were found between patients who had development of an infection and those who did not when the groups were compared with regard to the time from the injury to the first débridement, the time from admission to the first débridement, or the time from the first débridement to soft-tissue coverage. The time between the injury and admission to the definitive trauma treatment center was an independent predictor of the likelihood of infection. The time from the injury to operative débridement is not a significant independent predictor of the risk of infection. Timely admission to a definitive trauma treatment center has a significant beneficial influence on the incidence of infection after open high-energy lower extremity trauma.