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Background: The differential diagnosis between palmar psoriasis (PP), chronic hand dermatitis (CHE), and hyperkeratotic hand dermatitis (HHD) is challenging. Objectives: We sought to distinguish the histopathological and immunohistochemical characteristics between PP, CHD, and HHD. Materials & Methods: Hands, clinically diagnosed with PP, CHD, or HHD, were further evaluated using skin biopsy sections based on haematoxylin and eosin staining and immunohistochemical analysis for β-defensin 2 and interleukin-36γ. Results: Confluent parakeratosis, absent granular layer, and psoriasiform epidermal hyperplasia were more common in PP and HHD relative to CHE. The level of β-defensin 2 expression in the stratum corneum and interleukin-36γ in the stratum granulosum was higher in PP and HHD relative to CHD. Conclusion: Considering the similarities of histopathological and immunohistochemical findings, HHD may be an inflammatory disorder with a pathogenesis similar to that of PP, rather than CHD.