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Introduction: Despite good general and hematological tolerance, hydroxyurea frequently causes polymorphous skin lesions when given as long-term therapy. Distal skin atrophy, pseudodermatomyositis, pseudolichen and ulcerations have been observed., Case Report: We report three cases of diffuse atrophic collodion skin in patients given long-term hydroxyurea. Histology findings demonstrated atrophy and the same signs located at the dermo-epidermal junction as seen in acute toxidermia due to hydroxyurea. Examination of the ultrastructure showed abnormalities in the proliferative epidermal layer which was disrupted by edema and a multiple, irregular basal membrane., Discussion: The chronology of the lesions and partial resolution after treatment withdrawal together with clinical and histological signs demonstrating hydroxyurea impregnation would implicate hydroxyurea as the cause of this case of diffuse atrophic collodion skin. Cells in the epidermal layer of the skin, the most external layer in the organism, have a high turnover rate and would be more vulnerable to the cytostatic action of hydroxyurea than other tissues. The effect of hydroxyurea on keratinocytes implicated in the production and maintenance of the basal membrane would be one of the causes.