Clostridium A laboratory database was interrogated to identify patients developing CDAD after hip or knee replacement from January 2006 to December 2008. A database of arthroplasty patients was used to identify a control group of patients without CDAD to compare the effects of prescription of antibiotics for reasons other prophylaxis of deep infection, comorbidity and the use of gastroprotective agents. Eight patients developed CDAD. There were 1.7 cases of CDAD per 1000 joint replacements. Patients developing CDAD were more likely to have been prescribed additional antibiotics (p=0.047). There were no differences in the use of gastroprotective agents (p=0.703). A trial of a new prophylaxis regime would require 43,198 patients in each arm to show a reduction to 1 case per 1000 procedures. Cefuroxime based antibiotic prophylaxis is safe in patients undergoing elective joint replacement. Extremely large studies would be required to show marginal clinical benefits of new regimes. One prophylaxis policy will not suit all orthopaedic patient groups or procedures.