Paneth cells have been reported in colorectal adenomas and adenocarcinomas; however, the frequency of colonic Paneth cell-containing adenomas is unknown as are their clinicopathologic features. A total of 152 consecutive colorectal adenomas from 103 patients (57 males and 46 females) were reviewed. The frequency of Paneth cells in this cohort of adenomas was determined and correlated with patient demographics. Twenty-six adenomas (17.1%) from 22 (21.4%) patients harbored Paneth cells, which were not limited to the base of the crypts but aberrantly located throughout the crypts. Patient age, adenoma size, villous features, and grade of dysplasia were not different between these 2 groups. Not surprisingly, Paneth cell-containing adenomas were more likely to occur in the proximal colon (84.6% vs. 55.6%; P=0.006). There was a strong association between male sex and Paneth cell-containing adenomas, as 23 of 26 (88.5%) of these adenomas occurred in male individuals compared with 71 of 126 (56.3%) non-Paneth cell-containing adenomas (P=0.002). Upon review of an additional 460 adenomas from 200 patients with varying numbers of adenomas (68 with 1 adenoma, 68 with 2 adenomas, and 64 with 3 or more adenomas), the risk of harboring synchronous adenomas was associated with villous morphology, proximal location, and the presence of a Paneth cell-containing adenoma. Thus, the presence of a Paneth cell-containing adenoma may be a marker for increased risk of developing colorectal neoplasia.