objective. To determine the fraction of unnecessary antimicrobial use among patients with current and/or recent Clostridium difficile infection (CDI). design. Retrospective review from January 2004 through December 2006. setting. Minneapolis Veterans Affairs Medical Center (MVAMC). participants. Patients with new-onset CDI diagnosed at the MVAMC without another CDI diagnosis in the prior 30 days. methods. Pharmacy and medical records were reviewed to identify incident CDI cases, non-CDI antimicrobial use during and up to 30 days after completion of CDI treatment, and patient characteristics. Two infectious disease physicians independently assessed non-CDI antimicrobial use, which was classified as unnecessary if not fully indicated. Factors associated with only unnecessary use were identified through univariable and multivariable analysis. results. Of 246 patients with new-onset CDI, 141 (57%) received non-CDI antimicrobials during and/or after their CDI treatment, totaling 2,147 antimicrobial days and 445 antimicrobial courses. The two reviewers agreed regarding the necessity of antimicrobials in more than 99% of antimicrobial courses (85% initially, 14% after discussion). Seventy-seven percent of patients received at least 1 unnecessary antimicrobial dose, 26% of patients received only unnecessary antimicrobials, and 45% of total non-CDI antimicrobial days included unnecessary antimicrobials. The leading indications for unnecessary antimicrobial use were putative urinary tract infection and pneumonia. Drug classes frequently used unnecessarily were fluoroquinolones and /3-lactams. conclusions. Twenty-six percent of patients with recent CDI received only unnecessary (and therefore potentially avoidable) antimicrobials. Heightened awareness and caution are needed when antimicrobial therapy is contemplated for patients with recent CDI.