Patients with basal cell carcinoma and solar keratoses were treated with etretinate. Substantial and prolonged clinical improvement was seen. All patients with solar keratoses showed a decrease in the mean area and number of lesions and eight patients demonstrated complete healing clinically. Two patients experienced recurrence at 9 months after completion of treatment. Histometric and cell kinetic measurements on the epidermis of skin samples from these patients were performed. They revealed epidermal thickening and increased deoxyribonucleic acid (DNA) synthesis both in lesions and in clinically uninvolved skin following treatment. Assessments were also made of enzyme activities in lesions and uninvolved skin with the use of established quantitative cytochemical techniques. Significant reduction in levels of succinic dehydrogenase activity following etretinate treatment was detected in solar keratoses and in basal cell carcinomas. This was also the case for uninvolved skin of patients with solar keratoses. Glucose-6-phosphate dehydrogenase (G6PD) activity was significantly reduced following etretinate treatment in solar keratoses and in basal cell carcinomas, but uninvolved skin did not exhibit significant changes. These changes are in contrast to those previously reported in normal subjects, where the activity increased, but are similar to those observed in patients with ichthyotic disorders. The alterations in the cytochemical profile following administration of etretinate in the lesions of patients reported here are consistent with the view that the drug promotes a more normal pattern of epidermal differentiation. We favor the view that etretinate's antineoplastic action is exerted by preferentially allowing differentiation of normal epidermal cells and inhibiting dysplastic cells.