We previously reported a favorable histologic response of dysplastic nevi to topical tretinoin in three patients. To investigate the anticancer and cancer preventive effects of retinoids we have examined the effect of systemic isotretinoin on dysplastic nevi. After confirmatory baseline biopsies, eleven patients with the dysplastic nevus syndrome were treated with oral isotretinoin, 40 mg twice a day for 4 months. At completion of therapy, at least three previously identified and photographed clinically typical dysplastic nevi were rephotographed and removed for histologic evaluation. Eight patients completed the full course of medication. There were no clinical changes in the dysplastic nevi in these patients. Posttherapy biopsy specimens in six volunteers revealed most of the remaining lesions to be dysplastic nevi. The majority of lesions biopsied in two subjects showed normal, benign nevi only. This proportion of clinically typical dysplastic nevi that prove to be normal nevi histologically (28%) is not significantly different from that reported by others. Oral isotretinoin does not appear to have a significant biologic effect on the clinical or histologic appearance of dysplastic nevi in the treatment schedule employed.