OBJECTIVES: To assess potential implications of applying four competing national guidelines addressing antibiotic prophylaxis of Total Hip Replacement (THR) surgery. METHODS: Four guidelines were applied to a random sample of 386 medical records of patients who underwent THR surgery from January 1999 to December 2000. Setting: Orthopaedic surgery wards in a 2200-bed French teaching hospital. Main outcome measure: Compliance of physician practice with the French guideline (French National Agency of Accreditation and Health Evaluation), the Canadian guideline (Canadian Infectious Disease Society), the US guideline (Infectious Diseases Society of America), the South African guideline (South African Drug Action Programme) and the Belgian guideline (Belgian Hygiene Committee) was assessed by an independent investigator, according to the following criteria: antibiotic prophylaxis use, antimicrobial agent, dosage of first injection, time elapsed between first injection and incision, total duration of antibiotic prophylaxis. Interguideline agreement was assessed by using the Kappa coefficient. RESULTS: Overall compliance of physician practice varied widely from 69% of patients for the Canadian guideline to 16% for the Belgian guideline (compliance with the US guideline, the French guideline and the South African guideline was respectively: 62%, 53% and 19%) (Kappa=0.36; p<0.01). These variations were principally due to the differences between guidelines in the screening of Methicillin-Resistant Staphylococcus aureus (MRSA) carriage and in the choice of antimicrobial agent. CONCLUSIONS: Our findings emphasize substantial discrepancies between national guidelines from different countries. National experts should take into account evidence-based data when drawing up recommendations.