Antibiotic-associated Clostridium difficile diarrhoea may complicate surgery for proximal femoral fracture. We undertook a 4 year case control study to evaluate the effects of a change in antibiotic prophylaxis in our department. In the period January 2003 to January 2005, patients received three doses of cefuroxime (1.5 g). The new regimen is a single dose of cefuroxime (1.5 g) with gentamicin (240 mg) at induction. Prior to the change in prophylaxis, 912 patients underwent surgery for neck of femur fracture. Following the change, 899 patients underwent surgery over the period March 2005 to March 2007. 38 patients developed C. difficile infection (4.2%) in the initial group, compared with 14 patients (1.6%) in the group following the change in prophylaxis (P=0.009). Patients with C difficile infection also had a statistically significant increase in antibiotic exposure, inpatient stay, morbidity and inpatient mortality. The main challenges regarding antibiotic selection are failure of prophylaxis, often because of infection with MRSA, and C. difficile-associated diarrhoea as a consequence of antibiotic prophylaxis. Infection with C. difficile is reduced with the new regimen. We advocate the use of the new regimen as an effective alternative to multiple dose cephalosporins for the prevention of C. difficile infection in this group of high risk patients.