Background:Clostridium difficile (C. difficile) is a gram positive, spore forming organism usually transmitted by fecal to oral route. The mechanism of mucosal injury is related to its toxin producing activity, capable of inducing severe pseudomembrane formation and mucosal destruction. The use of antibiotics is a well-known risk factor for the development of C. difficile infection. However, the use of topical antibiotics such as silver sulfadiazine (SSD) is rarely associated with the infection; with only one case reported in the English literature. Case Presentation: A 60-year old white male came in for complains of abdominal pain for the past five days associated with abdominal bloating and constipation. PMH was significant for pemphigus vulgaris currently treated with 1% SSD as an adjunct to systemic steroids. Physical examination revealed a distended abdomen, decreased bowel sounds and mild tenderness to palpation. Rectal examination did not reveal any impacted stools, rectal masses and/or visible blood. Initial CBC showed leukocytosis of 17,000/mm3, with a highly significant left shift (28% bands). A subsequent CT of the abdomen revealed a considerable diffuse hypodense thickening of the colon with extensive stranding of the peri-colonic fat suggestive of pancolitis. Stool for C. difficile was subsequently sent, which later came back positive for the toxin. Blood cultures were drawn and he was started on metronidazole, vancomycin oral and vancomycin enema. Over the next three days, he started to develop loose watery stools on several occasions, associated with fever and chills. A repeat CT scan of the abdomen revealed prominent diffuse thickening of the colon with pericolonic inflammatory changes. A surgical evaluation was done, and a subtotal colectomy with ileostomy was performed. Histopathologic evaluation of the specimen revealed extensive pseudomembranous colitis. Clinical Significance: Topical SSD is believed to be absorbed in the system in higher quantities than expected. In a study by Wan et al on burn patients demonstrated a considerable increase of silver content in the blood within six hours after the application of SSD cream, more than 50 fold higher than the normal blood levels. In a similar study by Sano et al on experimental animals also demonstrated an increase in silver absorption on burned, denuded skin. Although topical antibiotics such as silver sulfadiazine has been considered relatively safe for the treatment of different skin infections, its chronic use might play a role in the suppression of the normal gut flora and the subsequent development of C. difficile colitis.