Objectives: A subset of colon cancers originates from sessile serrated adenomas/polyps (SSA/Ps). Our goal was to identify markers for SSA/Ps that could aid in distinguishing them from hyperplastic polyps (HPs). Methods: We performed immunostaining for gastric proteins MUC5AC and TFF1 in formalin-fixed, paraffin-embedded (FFPE) samples of HPs (n = 47), SSA/Ps (n = 37), and normal colon (n = 30). Results: Control mucosa expressed only trace amounts of MUC5AC and TFF1. HPs exhibited an 11.3- and 11.4-fold increase in MUC5AC and TFF1 expression confined to the upper segments of the crypts near the luminal surface of the polyps. SSA/Ps displayed on average 1.6-fold (MUC5AC, P < .008) and 1.4-fold (TFF1, P < .03) higher signal intensity for these markers than HPs, with a dramatic coexpression of MUC5AC and TFF1 typically occupying the entire length of the crypt. Immunoperoxidase results were similar to immunofluorescence staining for both MUC5AC and TFF1. Conclusions: Our results suggest that the analysis of expression of MUC5AC and TFF1 may be useful for differentiating SSA/Ps from HPs. We also suggest the possibility that crypt morphology may be at least partly due to overproduction of highly viscous gastric mucins and that these proteins may play a role in the serrated pathway to colon carcinogenesis.