Intercellular adhesion proteins are poorly characterized in acantholytic squamous cell carcinoma (ASCC), a more aggressive tumor than nonacantholytic invasive well-differentiated squamous cell carcinoma (SCC) of the skin. In this study we compared expression of Dsg3, E-cadherin, and syndecan-1 in ASCC and SCC. Immunohistochemical detection of Dsg3, E-cadherin, and syndecan-1 in 22 ASCCs and 22 SCCs was graded on a semiquantitative scale for intensity of staining (SI) and degree of circumferential staining (CS) about the cell membrane. Results were assessed by means of conditional logistic regression and χ2 analysis. Dsg3 and E-cadherin expression (SI, CS) was significantly decreased (P < .05) in ASCC compared with SCC, whereas staining for syndecan-1 was similar in the 2 tumor types. Differences in expression of adhesion markers between ASCC and SCC may contribute to the development of acantholysis in ASCC and its more aggressive biologic behavior.