Although the precise biological role of lysosomal membrane-associated glycoproteins (LAMPs) and ABH histo-blood group antigens (HBGAs) remains somewhat unclear, they are thought to be related to cell differentiation, cellular adhesion, and tumorigenesis. Here, we present the first comparative immunohistochemical study of both LAMPs and HBGAs in normal and neoplastic skin. Their localization is compared to that of high molecular weight cytokeratin and cytokeratin MNF 116. LAMPs and HBGA were differentially expressed in the normal stratified squamous epithelium, suggesting that they are involved in the initial steps of the differentiation process, whereas HBGAs are characteristic of terminal keratinocyte differentiation. No change in the reactivity for HBGA was detected in the stratified epithelium overlying squamous cell or basal cell carcinomas, whereas a considerable loss of LAMPs was detected. LAMPs were overexpressed in tumor cells, whereas HBGAs were lost in tumor zones of basocellular carcinomas. In spinocellular carcinomas, HBGAs were detected in tumor keratinocytes and in keratin pearls. These results provide new evidence for the differential expression of LAMPs and HBGAs in the normal stratified squamous epithelium, as well as the presence of a modulating reactivity in basocellular and spinocellular carcinomas, suggesting that these glycoproteins are involved in differentiation and tumorigenesis of human skin.