A double-blind, prospective randomized study was performed to compare cefazolin and cefonicid given for prophylaxis to 102 patients undergoing orthopedic surgery. Risk factors (e.g., age, sex, type of operation performed) among the two groups were similar. All patients had foreign material (prosthesis or other hardware) inserted at operation. There was a total of 6 infections (3 wound and 3 urinary tract) in 6 patients among the 48 receiving cefazolin (12.5%), whereas no infections were observed among the 54 patients who received cefonicid. Cefonicid, given once daily, provides protection against postoperative infection that is not inferior to cefazolin. A larger study is needed to confirm whether cefonicid is indeed superior to cefazolin.