Ten healthy women with moderate signs of facial photodamage (fine lines, wrinkles, dyspigmentations, hyperkeratotic prominent pores, and poor skin texture) applied imiquimod 5% cream once daily for 5 days each week for 4 weeks. None of the subjects had actinic keratoses or had received previous treatment for basal or squamous cell cancers. Histology, hydration, coloration, and imaging assessments were conducted before and after treatment to determine the effects of imiquimod therapy. Global assessments of the improvement in skin appearance were evaluated by subjects and a dermatologist. Histologic analysis revealed that the structurally regressive changes of the epidermis—atrophy, atypia, hyperchromatic nuclei, disorderly differentiation, and loss of polarity—were completely reversed after imiquimod treatment. The dermal matrix was unaffected by imiquimod therapy. Global assessments of skin appearance revealed that imiquimod treatment yielded appreciable reductions in wrinkles, dyspigmentations, and hyperkeratotic pores. Clinical improvements in skin appearance were confirmed by imaging, coloration, and hydration assessments that demonstrated a smoother surface, more uniform color, improved texture, and elimination of hyperkeratotic pores. The correction of epidermal dysplasia, a characteristic feature of photoaged skin in which epithelial tumors arise, suggests that imiquimod exerts a prophylactic action in the prevention of cutaneous tumors. Imiquimod provides an alternative to topical retinoids in reversing the clinical and histologically regressive changes of photoaged facial skin.