Four selenocysteine-containing proteins (gastrointestinal glutathione peroxidase, plasma glutathione peroxidase, selenoprotein P, and thioredoxin reductase-α) are expressed in the colonic mucosa. Because of their antioxidant functions, a protective role in colon carcinogenesis is discussed. The aim of this study was to elucidate an involvement of gastrointestinal selenoproteins during the adenoma-carcinoma sequence. Matched pairs of biopsies of colorectal adenomas and adjacent normal mucosa from 11 patients were analyzed for mRNA expression, protein expression, or enzyme activity of selenoproteins by Northern blot, Western blot, or enzymatic tests. All adenomas revealed a marked reduction of selenoprotein P and a variable increase of gastrointestinal glutathione peroxidase mRNA compared with adjacent tissue. Thioredoxin reductase-α and plasma glutathione peroxidase mRNA expression were not altered in adenomas. The Northern blot results were confirmed by Western blot analysis or enzyme activity measurement, respectively. We conclude that gastrointestinal glutathione peroxidase and selenoprotein P play a complementary role in the antioxidative cell defense along the adenoma-carcinoma sequence. It remains to be shown whether upregulation of gastrointestinal glutathione peroxidase in adenomas represents a compensatory mechanism to reduce susceptibility for oxidative damage resulting from the loss of selenoprotein P.