Collagenous colitis is a clinicopathologic syndrome characterized by chronic watery diarrhea and a mucosal inflammatory process with increased subepithelial collagen band on colonic biopsy. This disorder occurs primarily in females, and the etiology is unknown. We report the atypical presentation of collagenous colitis in two older-aged men following prolonged use of nonsteroidal antiinflammatory agents and short-term use of antibiotics. Although one patient had colonic pseudomembranes, neither patient had microbiological evidence of C. difficile toxin or infection. A variety of medications were initially given to these patients without resolution of diarrhea. Only after the diagnosis of collagenous colitis was made and antiinflammatory drugs directed at the colitis given did the diarrhea abate. These cases illustrate an unusual presentation of collagenous colitis with possible implications for pathogenesis.