Multiple actinic keratoses (MAK) are premalignant lesions that may produce a significant treatment problem not always controllable by destructive therapy. Etretinate therapy has been shown to produce both prophylactic and therapeutic effects on premalignant epithelial tumors of mice. Results are presented on an 8-month double blind crossover trial (4 months placebo/4 months etretinate, randomly assigned) in 15 patients with severe MAK. Fourteen patients improved significantly on etretinate, whereas five of six patients who had placebo in the first 4-month period became worse as measured by the number of lesions and diameter of larger lesions. However, eight of nine patients who had placebo in the second 4-month period (ie, following etretinate therapy) showed no significant increase in the number of actinic keratoses, suggesting that etretinate may prevent the appearance of new lesions during, and for some time after, its administration. Moderate dose-dependent mucocutaneous side effects were frequent. It is proposed that an annual 3-month course of etretinate may help control severe MAK patients, minimizing the need for destructive therapies.