Previous studies have shown that hyperplastic and serrated polyps of the colon show variable degrees of gastric and intestinal differentiation. MUCs are a class of approximately 20 genes that encode high-molecular-weight glycoproteins, or mucopolysaccharides, that are widely expressed in epithelial cells and show organ specificity. The role of MUC in serrated carcinogenesis is unknown. One previously published study suggested that expression of MUC6 is specific for sessile serrated adenoma/polyps (SSA/Ps) and thus can be used to distinguish these lesions from hyperplastic polyps (HPs). However, data from our group suggest that MUC antibodies are not reliable in this differential diagnosis. The aims of this study were to systematically evaluate the expression of MUCs in serrated colon polyps and to determine the efficacy of MUC expression in differentiating HPs from SSA/Ps specifically. Routinely processed specimens from 182 serrated polyps [58 HPs, 46 SSA/Ps, 59 SSA/Ps with dysplasia (SSA/P-D), 19 traditional serrated adenomas, and 38 conventional tubular or tubulovillous adenomas (CAs)] were immunohistochemically stained with MUC1, MUC2, MUC5AC, and MUC6, and scored for extent, intensity, and location of staining within the polyps. HPs were further subclassified into goblet cell type (N=18), microvesicular type (N=21), and mucin-depleted type (N=19). The data were compared between the different polyp groups and between polyps from different anatomic locations in the colon. MUC1, MUC2, MUC5AC, and MUC6 were expressed in 27%, 100%, 100%, and 72% of serrated polyps overall. These antibodies were positive in 32%, 100%, 100%, and 43% of CAs. Expression levels of MUC1, MUC2, and MUC5AC were not significantly different between any of the polyp subgroups or between serrated polyps and CAs. Both SSA/P and SSA/P-D showed a significantly higher percentage of polyps that stained with MUC6, and a greater degree and intensity of staining for this peptide in comparison with HPs. Overall, 91% of SSA/Ps and 84% of SSA/P-Ds were positive for MUC6 in comparison with 60% of HPs (P<0.001 and P=0.02, respectively). Although polyps from both the left and right colon from each polyp group showed positivity for MUC6, a significantly higher proportion of SSA/P-Ds and traditional serrated adenomas from the right colon showed MUC6 positivity compared with those from the left. No differences were noted in MUC6 staining between each of the 3 HP subgroups. On the basis of these data, we conclude that SSA/P and SSA/P-D show increased expression of MUC6 compared with HPs; however, because of overlap in the presence, degree, and intensity of staining, use of MUC6 to differentiate HPs from SSA/P or SSA/P-D in individual cases is not reliable because of a lack of specificity. Differences in MUC6 expression between right-sided and left-sided colonic polyps supports the theory that there may be biological differences in the progression of malignancy in different portions of the colon with regard to the serrated pathway of carcinogenesis.