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Cefazolin is the current recommendation for antibiotic prophylaxis in orthopaedic surgery. However, reported cross-reactivity to first generation cephalosporins in patients with a penicillin allergy ranges from 4% to 18%. In their reports on the rates of cross-reactivity, previous authors have not distinguished IgE from non-IgE reactions. The purpose of this study was to determine the various reactions that are reported as a penicillin allergy and the rate of cefazolin cross-reactivity in patients having only non-IgE reactions to penicillin.This is a prospective case study of consecutive patients undergoing orthopaedic surgery that had indications for prophylactic antibiotics over a 4-year period. The patients’ self-reported specific allergic reactions to penicillin were noted. The reactions were characterized as either IgE or non-IgE mediated. Non-IgE mediated penicillin allergic patients were given cefazolin in the operating room under a controlled setting. Any adverse reaction after the administration of cefazolin was recorded.There were 801 patients. The prevalence of a reported penicillin allergy was 14.1%. Non-IgE mediated reactions accounted for 73.5% of patients reporting a penicillin allergy. Of the 81 non-IgE mediated penicillin allergic patients who received cefazolin, no adverse reactions were reported.It is important to obtain the specific reaction in patients reporting that they are allergic to penicillin to guide the choice of antibiotics. In patients who report a non-IgE reaction to penicillin, it is safe to administer cefazolin.