Clostridium difficile-associated diarrhea is a recognized postoperative complication. However, the exact risk factors for this condition after total joint arthroplasty (TJA) remain unknown. This case-controlled study intended to identify the predisposing factors for this condition. There were 16 cases of C difficile infections after 9880 TJA (0.16% incidence) between January 2001 and May 2006 at our institution. The cases were matched with 32 controls for month/year of surgery and surgeon. This study suggests that patients with deteriorated physical status or those who receive greater than one antibiotic after surgery are at a higher risk for developing C difficile-associated diarrhea after TJA.