In an open trial, five patients with lamellar ichthyosis showed no response to four weeks of treatment with oral cyclosporine (cyclosporine A) (6 mg/kg/d). Histologic examination of lamellar ichthyosis revealed hyperkeratosis; psoriasiform acanthosis; dilated, tortuous capillaries; and a slight perivascular lymphocytic infiltrate. Immunofluorescence studies revealed, in the epidermis, normal numbers of T6+DR+ Langerhans' cells and an absence of T cells and intercellular adhesion molecule-1 expression. In the papillary dermis, there were prominent capillaries as detected by staining with anti-factor VIII-related antigen. The endothelial cells also expressed large amounts of HLA-DR and intercellular adhesion molecule-1, suggesting that they were activated. Only occasional Langerhans' cells were found in the dermis. Histologic and immunofluorescence findings were unchanged with cyclosporine therapy. The effects of cyclosporine on lamellar ichthyosis are contrasted with those reported for psoriasis. Since lamellar ichthyosis and psoriasis share similar features of epidermal hyperproliferation and the presence of activated, dilated, tortuous vessels, but differ in the lack of immunologic cellular activity, their contrasting response to cyclosporine suggests that the target of the action of cyclosporine is the immune system rather than the keratinocyte or the endothelium. However, other factors may have to be considered.