Antibiotic prophylaxis for joint replacement surgery is widely recommended and has been shown to reduce infection rates. Cephalosporins have commonly been used but are associated with development of Clostridium difficile associated diarrhoea (CDAD) The purpose of this study was to assess whether a change of protocol aimed at reducing CDAD, including a change of antibiotic prophylaxis would reduce rates of CDAD and other postoperative complications. We studied all 7989 patients in our trust that underwent hip or knee replacement from May 2002 to March 2009. These patients fell into two cohorts, firstly those who were prescribed cefuroxime as prophylaxis and secondly those prescribed gentamicin which was introduced following national concern regarding CDAD. Following the change of prophylaxis from cefuroxime 750mg three doses to gentamicin 4.5 mg/kg single dose the rate of CDAD reduced significantly (0.17% to 0%, p<0.03), however the rate of acute renal failure (0.29% to 0.6%, p=0.04) and pneumonia (0.71% to 1.38%, p<0.01) increased significantly. The rate of urinary tract infection (1.44% to 1.20%, p >0.05) and the overall return to theatre rate (1.86% to 2.30%, p=0.21) were not significantly changed. The spectrum of bacteria grown from infected joint replacements in the two cohorts was also analysed. The rate of deep MRSA infection was significantly less in the group given gentamicin. The frequency of other bacteria was also different between the cohorts, but not significantly so. We conclude that changing protocol including antibiotic prophylaxis in joint replacement patients can have the desired effect on a particular outcome namely CDAD but can also result in increased rates of other postoperative complications. It is also likely to result in a change in the bacterial spectrum of infected joint replacements.