Photodamaged skin is characterized clinically by coarseness, telangiectasia, wrinkling, discrete hyperpigmented and hypopigmented macules, atrophy, and ultimately the development of neoplasms. Studies on the UVB-irradiated hairless mouse indicate that topical application of tretinoin or isotretinoin induces structural modifications at the dermal level. Clinical trials indicate that tretinoin improves skin appearance in patients who have photodamage. This double-blind, vehicle-controlled clinical trial was conducted to determine whether 36 weeks of treatment with topical isotretinoin improves mildly to moderately photodamaged facial skin. After they gave written informed consent 776 patients were randomly assigned to 36 weeks of treatment with either vehicle cream or isotretinoin cream, applied once nightly. Efficacy was evaluated by means of physician and patient assessment and a blinded analysis of standardized photographs taken before and after treatment. When compared with vehicle, treatment with isotretinoin resulted in statistically significant improvement in overall appearance, fine wrinkling, discrete pigmentation, sallowness, and texture. Isotretinoin cream was well tolerated.