A prospective, randomized, double-blind study was conducted to determine if estradiol and glycolic acid creams produced a significant reversal of epidermal and dermal markers of aging and if the cumulative effect of the creams was greater than either alone. Sixty-five patients applied a cream containing 0.01% estradiol or 15% glycolic acid, alone or in combination, to one side of the face, and a vehicle cream to the opposite side, for 6 months. A 2-mm punch biopsy was obtained from the hairline of each patient and processed for analysis. The estradiol treatment produced a 23% increase in epidermal thickness (P = .00458); the glycolic acid, a 27% increase (P = .00467); and the combination, a 38% increase (P = .000181). All groups showed a statistically significant improvement in reversing markers (rete peg pattern, epidermal thickness) of skin aging. Although not statistically significant (P = .1), a cumulative effect was seen when estradiol and glycolic acid creams were used in combination.