A model was developed to identify and compare the local wound factors that induce acute osteomyelitis in a prospective, controlled investigation. When compared with wounds containing either virulent bacteria or dead bone, statistical analysis disclosed a significant increase in the incidence of osteomyelitis when virulent bacteria and dead bone were combined. The incidence of osteomyelitis in wounds containing an inoculated, hematoma-filled dead space was significantly less when compared with wounds containing dead bone and virulent bacteria. The incidence of osteomyelitis is significantly less when a nonvirulent strain of bacteria is substituted for a virulent strain. Although rigid internal fixation increased the incidence of osteomyelitis to 100% and long-term antibiotic therapy decreased the incidence, these changes were not statistically significant. These data allow the authors to predict the relative risk of osteomyelitis when these wound factors are present. The prevention of osteomyelitis depends on the clinical identification and modification of these local wound factors.