Clostridium difficile-associated disease (CDAD) is the most common cause of nosocomial diarrhea. Information about CDAD in solid organ transplant (SOT) recipients is scarce. To determine its epidemiology and risk factors, we conducted a cohort study in which 4472 SOT patients were prospectively included in the RESITRA/REIPI (Spanish Research Network for the Study of Infection in Transplantation) database between July 2003 and July 2006. Forty-two episodes of CDAD were diagnosed in 36 patients. The overall incidence was 0.94%. Median onset of infection was 31.5 days (range 6–741); in half the cases, onset occurred during the first month after transplantation. In 26% of cases, there was no previous antibiotic use. Independent risk factors for CDAD using Cox regression analysis were previous use of first- and second-generation cephalosporins (HR 3.68; 95%CI 1.8–7.52; P < 0.001), ganciclovir prophylactic use (HR 3.09; 95%CI 1.44–6.62; P = 0.004) and corticosteroid use before transplantation (HR 2.95; 95%CI 1.1–7.9; P = 0.031). There were no deaths related to CDAD. In summary, the incidence of CDAD in SOT was low, most cases were diagnosed soon after transplantation and the prognosis was good.