The mean number of cases of Clostridium difficile diarrhea at the Minneapolis Veterans Administration Medical Center increased to 17.3 per month in June-August 1985, compared with 7.1 per month in the previous 17 mo. Plasmid profiles and clindamycin susceptibility were used as markers to evaluate the increase in cases. Ninety clindamycin-resistant and 22 clindamycin-susceptible isolates of C. difficile from 1985 were examined for plasmids. A clindamycin-resistant organism contained a cryptic plasmid of 3.1 kilobases (kb). None of the clindamycin-susceptible isolates contained the 3.1-kb plasmid, as compared with 40 of 90 clindamycin-resistant isolates (P less than .005). Restriction endonuclease digestion and Southern blot hybridization were used to confirm the identity of the 3.1-kb plasmid between strains. Isolates retained clindamycin resistance after plasmid curing. It could not be determined if the organism responsible was an indigenous C. difficile strain that acquired a plasmid or was a new strain introduced from outside the hospital.