Antibiotic prophylaxis is routinely administered during joint replacement surgery and may predispose patients to Clostridium difficile-associated disease (CDAD). The primary aim of this study was to determine the incidence of this following joint replacement, using a cefuroxime-based regimen. Patients developing CDAD were compared with a control group of patients without CDAD. The incidence of the former was 1.7 per 1000 primary joint replacements. Those patients prescribed additional antibiotics had a higher incidence of CDAD (p = 0.047), but there was no difference between the two groups in relation to the use of gastroprotective agents (p = 0.703). A trial of a new prophylaxis regimen would require 43 198 patients in each arm to show a reduction of one case per 1000 procedures. Cefuroxime-based antibiotic prophylaxis is safe in patients undergoing primary elective joint replacement.