Hereditary skin disorders resulting from desmosome gene pathology may preferentially involve the palms and soles. Why this is so is not clear. Moreover, even in normal control skin it is unknown whether there are differences in desmosome number, size or structural organization in palmoplantar sites compared with skin from other body regions. Therefore, we sought evidence for such differences by examining desmosome expression in relation to epidermal differentiation in both epidermis and cultured keratinocytes from normal human palm and breast skin samples. Confocal microscopy of skin biopsy material showed relative differences in the expression profiles of several desmosomal proteins (desmogleins, desmocollins, desmoplakin, plakoglobin and plakophilin 1) between the two sites. Western blotting revealed a higher expression level of all five proteins in palm compared with breastcultured keratinocytes. Staining for the differentiation-associated component, involucrin, suggested an earlier onset of synthesis of this protein in palm epidermis, and a suspension-induced differentiation assay showed that involucrin synthesis began earlier in palm keratinocytes than in breast cells. At 4-8 h, the number of involucrin-positive cells in palm keratinocytes was almost twice that in breast. Morphometric analysis showed that, overall, desmosomes were larger but of similar population density in the palm compared with breast skin. These findings demonstrate differences in desmosome structure and protein expression between the two sites, possibly reflecting the needs of palms and soles to withstand constant mechanical stress. They may also help to explain the preferential involvement of this region in certain hereditary disorders (palmoplantar keratodermas), associated with mutations in desmoplakin or desmoglein 1.