Six hundred and eleven patients undergoing surgical resection and endoprosthetic reconstruction for lower extremity bone tumors were randomized to receive a one-day regimen (n=312) or five-day regimen (n=299) of post-operative prophylactic intravenous antibiotics. The primary outcome was surgical site infection as classified according to the criteria established by the Centers for Disease Control and Prevention (CDC), within one year of surgery. Secondary outcomes of interest included antibiotic-related complications, unplanned re-operations, oncologic and functional outcomes, and mortality. There was no significant difference in surgical site infections between the two intravenous antibiotic regimens. However, the five-day regimen group had significantly more antibiotic related complications compared to the one-day regimen group. No differences in other secondary outcomes were found.