Oral isotretinoin (ISO) is the only drug which promotes prolonged remission or cure of severe acne. It also has other properties, supporting its use for non-acne indications. Retinoic acid (RA) is gold standard treatment for photoaging. ISO for photoaging treatment was reported in non-controlled trials as alternative to RA, which causes skin irritation. To compare clinical, histological, and immunohistochemical effects of low-dose ISO and 0.05% topical RA to treat photoaging. Randomized, comparative, evaluator-blinded, single-center study. Twenty-four healthy, Caucasian, 50 to 75-year-old men and women (menopausal or sterilized) with advanced photoaging were included. Twelve subjects received ISO, 20 mg/day, and 12 subjects were treated with RA cream, for six months; both treatments were administered every other day, and moisturizer and sunscreen were also used. Outcome measures included patient assessments, blinded photographic evaluations, Life Quality Index, histological (HE, Verhoeff) and immunohistochemical (p53, collagen type I) evaluations, adverse events, liver function, lipid profile, and blood count. Statistical analysis with generalized estimating equations and repeated measures ANOVA tests was used. Eleven subjects in each group completed the study. Patient and photographic assessments showed overall improvement in skin appearance. Quality-of-life scores were reduced for all subjects. Histological analysis revealed corneal layer diminution, epidermal thickness increase, and elastosis reduction. Immunohistochemical findings revealed significant epidermal p53 reduction and dermal collagen 1 increase. No differences were found between groups; laboratory tests showed no significant alterations. Despite being safe and effective, low-dose ISO was not superior to 0.05% RA for advanced photoaging treatment.