Hereditary mixed polyposis syndrome (HMPS), characterized by hyperplastic, juvenile, admixed, serrated adenomas and eventually colorectal cancer, is managed by repeated polypectomy and surgery. We determined if HMPS polyps express cyclooxygenase-2 (COX-2). Nineteen recent HMPS polyps, from five family members, were stained for COX-2. Polyps' epithelium and stroma and comparison tissues (normal colonic mucosa [9], sporadic juvenile polyps [18], colorectal cancers [3]) were quantified for COX-2 by: area of staining (0-3) x intensity (0-3). Epithelial, stromal, and total scores were evaluated in relationship to histology and dysplasia. HMPS polyps COX-2 mean epithelial (5.0+/-3.0), stromal (6.9+/-1.9), and total (11.8+/-4.6) scores were significantly higher (P < 0.01) than sporadic juvenile polyps (0.6+/-0.7, 3.1+/-2.2, and 3.6+/- 2.2 respectively), while colorectal cancer scored 9, 9, and 18. There was a positive association (P < 0.01) among histology, degree of dysplasia, and COX-2 expression. COX-2 expression in HMPS polyps and its association with dysplasia suggest that chemoprevention might be a useful adjunct therapy.