Clear cell change is seen in <1% of colonic tubular adenomas (TAs) and remains incompletely characterized. Associated adenocarcinomas can also demonstrate a clear cell phenotype. Eleven TAs with at least focal clear cell change with or without associated invasive adenocarcinoma, from 10 patients were studied. The lesions were stained with periodic acid-Schiff (PAS)/PAS-diastase and immunolabeled with antibodies to MUC2, MUC5AC, MUC6, CK7, CK20, and CDX2. Eight of 11 (77%) TAs with clear cell change had focal to extensive high-grade dysplasia. Two were associated with invasive clear cell adenocarcinoma. The adenomas and adenocarcinomas ranged from 0.5 to 3.5 cm. PAS/PAS-diastase stains showed minimal PAS(+) material in the clear cells. On immunohistochemical studies, the clear cells had decreased MUC2 labeling compared with the surrounding conventional adenoma in 9 of 11 (88%) cases, including the 2 clear cell adenocarcinomas. In 3 of the 11 lesions, the background TA showed at least focal MUC5 immunoreactivity, their associated clear cell area had decreased MUC5 labeling in all 3 cases. No immunoreactivity to MUC6 was observed in the background TAs and clear cells in all cases. Compared with background TA, both increased and decreased expression of CK7, CK20 (in quantity), and CDX2 (in intensity) were observed in the clear cells of TAs and adenocarcinomas. One of the clear cell adenocarcinomas was CK20, CK7, CDX2 and the other was CK20, CK7, CDX2-focal positive. Thus, although the clear cells have different MUC protein profiles than the background adenomatous epithelium, invasive clear cell adenocarcinomas retained the typical CK20(+)/CK7(-) profile of conventional adenocarcinomas. Our results indicate that clear cell adenocarcinomas can be primary to the colorectum with identifiable precursors. Awareness of them and their immunoprofile allows distinction from clear cell lesions from other sites.