The calmodulin content of epidermis was determined by assay of biologically active and radioimmunoassayable calmodulin in epidermal biopsy samples of 16 normal control subjects and 36 patients with psoriasis. Calmodulin levels in the involved epidermis of patients with psoriasis were significantly greater than in epidermis of control subjects, with both methods of calmodulin measurement. Levels of calmodulin in the uninvolved epidermis were also elevated but to a lesser degree, achieving statistical significance only when measured by radioimmunoassay. However, the degree of correlation between the two measurements of calmodulin was poor for the patient samples, suggesting that each may measure a different form of calmodulin. The specificity of the elevated calmodulin in psoriatic epidermis was investigated by measuring calmodulin in another unrelated tissue. Calmodulin activity in circulating peripheral blood lymphocytes of seven patients with psoriasis was similar to that found in the lymphocytes of ten normal volunteers. The relationship between calmodulin and the hyperproliferative state of the psoriatic epidermis was investigated. No significant increase in calmodulin activity was found after mitogen stimulation of lymphocyte proliferation or after Sellotape-stripping of the epidermis by a protocol which has been shown to cause hyperproliferation of the epidermis.