Antitumoral agents, especially when administered in combination, can induce pseudomembranous colitis, due to their antimitotic and antibacterial properties. Although patients given 5-fluorouracil frequently show nonspecific colitis or diarrhea without colitis, very few cases of proven pseudomembranous colitis have been described during 5-fluorouracil monotherapy. We describe the second case reported in the English literature of a typical pseudomembranous colitis occurring in a patient given 5-fluorouracil as a single antimitotic agent for colonic cancer. Intestinal injury was not preceded by antibiotic therapy. Although both stool and pseudomembrane culture did not yield C. difficile, oral vancomycin was started. This treatment led to a prompt improvement of intestinal symptoms and colitis was resolved in one week.