It has been previously shown that S100A2 is downregulated in tumor cells. The level of immunohistochemical S100A2 expression was therefore characterized in 424 normal and tumoral (benign and malignant) tissues of various origins, but mostly epithelial (with either glandular, squamous, respiratory or urothelial differentiation). We also investigated whether S100A2 could be co-localized with cytokeratin K14, an intermediate filament protein expressed in basal proliferative keratinocytes. Our data show that S100A2 has a low level of expression in non-epithelial tissue. In epithelial tissue S100A2 expression decreases remarkably in the tumors when compared to the normal specimens, and was correlated with the level of keratin K14. This decrease in S100A2 staining from normal to cancer cases is more pronounced in glandular than in squamous epithelial tissue. In addition, the patterns of S100A2 staining also differ between glandular and squamous tissue. These data suggest distinct functional roles for S100A2 in epithelial tissue of squamous or glandular origins.