Recurrent Clostridium difficile diarrhea (RCDD) occurs in 20% of patients after they have received standard antibiotic treatment with vancomycin or metronidazole, but the reasons for the recurrences are largely unknown. Patients receiving vancomycin or metronidazole for active C. difficile diarrhea (CDD) were referred to our study centers for treatment and a 2-month follow-up as part of a randomized placebo-controlled trial. Sixty patients had RCDD (median number of episodes, 3.0; range, 2-9 episodes) and 64 were having their first episode of CDD. Patients with RCDD had more-severe abdominal pain and were more likely to have fever but initially responded well to antibiotic therapy. Data on sequential episodes showed no progression in disease severity. Five factors were associated with a higher risk of RCDD: the number of previous CDD episodes, onset of the initial disease in the spring, exposure to additional antibiotics for treatment of other infections, infection with immunoblot type 1 or 2 strains of C. difficile, and female gender. These factors may help to identify patients who are more likely to develop RCDD and require careful medical supervision.