Diminutive hyperplastic polyps are the most common non-neoplastic lesions of the colon. Typically, they are small (< 0.5 cm) sessile lesions, lack cellular atypia, and are found predominantly in the rectosigmoid region of the colon. Multiple large hyperplastic polyps (> 1 cm) are rare. Although the relationship between diminutive hyperplastic polyps and adenomatous polyps or carcinoma is controversial, even less data are available on the significance of large hyperplastic polyps. We report the case of a 56-yr-old man who was seen because of fatigue, anemia, and Hemoccult-positive stool. On air contrast barium enema study and colonoscopy, multiple polyps that were similar in appearance were found distributed symmetrically throughout the colon. However, histologic examination revealed 16 hyperplastic polyps 1-2 cm in size, multiple diminutive hyperplastic polyps, one adenomatous polyp, and one adenomatous polyp containing well-differentiated adenocarcinoma. Because multiple large hyperplastic polyps are rare, we suspect this entity may be distinct from diminutive hyperplastic polyps. In our patient, large hyperplastic polyps were distributed symmetrically throughout the colon and were associated with a synchronous carcinoma. Because large hyperplastic polyps may be coincident with adenomatous polyps and carcinoma of the colon, we recommend that patients found to have large hyperplastic polyps undergo removal of all polyps for histologic study.