Many people are interested in addressing visible signs of aging with non-invasive cosmetic treatments. Development of effective topical products will provide options to delay or support cosmetic procedures. This study assessed and compared the efficacy and tolerance of a topical product used over the course of 16 weeks to a single ablative laser treatment on women with moderate global photodamage on the face. Subjects in Cell 1 (Laser Cell) were treated over the entire face with a fractional CO2 laser system. Subjects in Cell 2 (Topical Serum Cell) were treated with a topical serum containing hydroxypinacolone retinoate and peptides over the entire face, twice per day for 16 weeks. The study was composed of 71 women, with 29 in the Laser Cell (mean age 56.2) and 42 in the Topical Serum Cell (mean age 55.0), between 40 and 65 years old. Expert grading was used to determine efficacy parameters. Participants in the Topical Serum Cell achieved more significant improvement (p < 0.05) in Marionette lines, fine lines (global face), wrinkles (global face), wrinkles (crow's feet), nasolabial folds, texture, smoothness (tactile), global hyperpigmentation, lift, and photodamage compared to participants in the Laser Cell. Participants in the Topical Serum Cell achieved parity in the look of fine lines (crow's feet), forehead lines, glabella, firmness/bounce (tactile), skin tone evenness, radiance. While no statistically significant differences in tolerability were observed, treatment with the topical cosmetic product achieved parity or statistically better improvement in parameters compared to laser treatment at 16 weeks.