E-cadherin is a calcium-dependent cell-cell adhesion molecule expressed by melanocytes and responsible for their adhesion to keratinocytes in vitro. In this study, the expression of E-cadherin and its associated cytoplasmic proteins alpha-, beta-, and gamma-catenin was evaluated in melanocytic lesions by immunohistochemistry. E-cadherin expression was evaluated in 70 malignant melanomas and the catenins in 35 of these specimens. Twenty benign melanocytic naevi were also evaluated for E-cadherin and catenin expression. In normal epidermis, E-cadherin/catenin immunostaining was localized at the intercellular borders. In melanomas, a differential loss of E-cadherin expression was observed. Membranous E-cadherin staining was absent in dermal nests of melanomas in their radial growth phase and in Clark level II and III lesions, whereas it was present in a high proportion of melanomas in their vertical growth phase, in Clark level IV and V lesions and in metastasizing melanomas. In contrast, superficial compartments of naevi showed membranous E-cadherin immunoreactivity and junctional naevus cell nests displayed heterogeneous or diffuse cytoplasmic staining. Cytoplasmic alpha- and beta-catenin, but not gamma-catenin staining were detected in all benign and malignant lesions. These findings indicate that qualitative changes in the expression and cellular localization of E-cadherin and of alpha-, beta-, and gamma-catenin occur in melanocytic lesions and may reflect different stages in their progression.