Open fractures are highly incident injuries closely related to the modern life, in which accidents caused by motor vehicles or other machines impart high energy to bone tissue. Individual morbidity is represented by the functional impairment resultant of infection, nonunion, or vicious healing. In terms of public health, there are huge costs involved with the treatment of these fractures, particularly with their complications. One of the critical issues in managing open fractures is the use of antibiotics (ATB), including decisions about which specific agents to administer, duration of use, and ideal timing of the first prophylactic dose. Although recent guidelines have recommended starting antibiotic prophylaxis as soon as possible, such a recommendation appears to stem from insufficient evidence. In light of this, we conducted a systematic review, including studies that addressed the impact of the time to first antibiotic and the risk of infectious outcomes. Fourteen studies were selected, of which only four found that the early initiation of treatment with antibiotics is able to prevent infection. All studies had important risks of bias. The results indicate that this question remains open, and further prospective and methodologically sound studies are necessary in order to guide practices and health policies related to this matter. Level of Evidence II; Therapeutic Studies Investigating the Results Level of Treatment.