A prospective, randomized study was performed on 75 Gustilo Grades II and III open fractures to determine the efficacy of once daily, high dose aminoglycoside therapy, compared with more conventional dosing, in reducing the infection rate when used in conjunction with an aggressive operative treatment protocol. All patients enrolled in the study were treated with immediate irrigation, debridement, operative stabilization of the fracture, and 1 g of cefazolin every 8 hours. At the time of admission patients were randomized to two groups. Patients in Group I received gentamicin 5 mg/kg divided into twice daily doses, and patients in Group II received gentamicin 6 mg/kg given once daily. All patients were monitored for renal toxicity and observed for radiographic and clinical signs of infection until fracture union. The results of the study revealed no statistically significant difference between once daily, high dose versus divided, low dose gentamicin in infection rates. Thus, daily dosing of gentamicin was found to be safe, effective, and cost efficient in the treatment of open fractures when combined with a cephalosporin and aggressive operative debridement and stabilization.