There have been a worldwide change in the susceptibility patterns of antibiotics by many community-acquired microorganisms including those associated to wound infection after open fractures. However, the current antibiotic prophylaxis practice adopted by orthopedic surgeons to prevent infectious complications following open fractures has not changed, since Gustilo and Andersen classification was published several decades ago. Few studies have addressed the current pattern of infectious organisms identified in open fracture wounds and its susceptibility to antibiotics that have been empirically used. We aim to study the incidence of community-acquired resistant organisms isolated in lower extremities open fracture and analyze if antibiotic therapy based upon identified resistant pathogens, would decrease surgical site infection (SSI) rates. In a prospective, single center cohort study, from August 2013 to March 2015 at a tertiary public university institution, 136 subjects presenting Gustilo type II or III lower extremities open fractures were randomly assigned in two arms. Both arms were submitted to surgical debridement, fracture stabilization, and empirical antibiotic therapy, but subjects on Group II had at least three samples of tissue cultures collected during debridement. Patients previously treated at an emergency department other them ours were excluded. When resistant bacteria was identified, antibiotic therapy was modified according to antibiogram tests. The primary outcome was to compare the infection rates between these two groups, after early 60-days follow up. We included 136 patients with Gustilo-II (43.4%), –III, (34.5%) open fractures, of which 86% were male, with median age of 33.7 years, and 69.1% presented no comorbidities. Group II (collection of tissue cultures) accounted 36.7% of patients, and among them bacterial growth were detected in 36% (16/50). Microorganism resistant to empirical antibiotic therapy was identified in 18% (9/50), including Staphylococcus aureus, coagulase-negative Staphylococci, Enterococcus sp, Pseudomonas aeruginosa, Klebsiella sp, Serratia sp, Escherichia coli, and Enterobacter sp. Median duration of antibiotic treatment was eleven days. During 60-days of follow up, 71 patients (52.2%) were evaluated for signs of infection using the Centers for Disease Control and Prevention criteria, of which 63.4% (45/71) and 36.6% (26/71) were on Group I and II, respectively. No significant difference in the rates of SSI was observed between the study arms (19.2% vs 22.2%, respectively, P = 0.95). We detected higher rates of bacterial resistance on Gustilo type II and III open fracture wounds, but adjusting antibiotic therapy towards these contaminants did not affected the rates of infection afterwards.