The epidemiology of clinically recognized community-acquired Clostridium difficile-associated diarrhea was assessed in a retrospective cohort study of members of a health maintenance organization (HMO). Potential cases were identified through positive toxin assay results and confirmed by review of automated full-text medical records. Of 51 cases identified (7.7 per 100,000 person-years), 42 (82%) were diagnosed and treated exclusively in the ambulatory care setting; 33 cases occurred within 42 days after 494,491 exposures to antibiotics dispensed by an HMO pharmacy. Antibiotic-specific attack rates varied from 0 to 2040 cases per 100,000 exposures. Increased age was associated with C. difficile-associated diarrhea (P < .001). Age-adjusted antibiotic-specific attack rates were at least 10-fold higher (P < .05) for nitrofurantoin, cefuroxime, cephalexin plus dicloxacillin, ampicillin/clavulanate plus cefaclor, and ampicillin/clavulanate plus cefuroxime than for ampicillin or amoxicillin; several other antibiotics were associated with similar but not significantly increased risks.