Clostridium difficile-associated diarrhea (CDAD) remains a significant problem in surgical patients. To address this, we prospectively studied all episodes of treated CDAD in surgical inpatients at the University of Virginia hospital from December 1996 through March 1998. CDAD accounted for 3.2 per cent (32) of 1000 total infections. Compared with a randomly selected control group with other nosocomial infections, patients with CDAD had a longer period from the time of admission to diagnosis of infection (19 +/- 4 versus 9 +/- 1; P = 0.01), were more likely to be female (66% versus 37%; P = 0.009), and had a higher overall crude mortality (31% versus 11%; P = 0.01), although there were no deaths directly attributable to CDAD. Ciprofloxacin (19%) and cefoxitin (16%) were the most common individual antibiotics prescribed before the diagnosis of CDAD. The average time from completion of antibiotic therapy to diagnosis of CDAD was 7 +/- 2 days (range, 0-58). Sixteen per cent (5 of 32) developed CDAD after administration of prophylactic perioperative antibiotics only. The high crude mortality rate associated with CDAD suggests that this may be a significant predictor of poor outcome among infected surgical patients. Antibiotics used commonly but not classically associated with CDAD frequently precipitate this infection. Finally, the use of prophylactic antibiotics is not without risk, as demonstrated by the significant percentage of CDAD occurring after routine administration of these agents.