Background: Adapalene is a new naphthoic acid derivative developed for the topical treatment of acne vulgaris. Objective: We compared the skin tolerance of adapalene 0.1% gel with tretinoin 0.025% gel in subjects with acne. Methods: Fifteen acne patient volunteers were enrolled in this investigator-masked, left-right comparison, randomized, controlled, intraindividual study. Adapalene 0.1% gel and tretinoin 0.025% gel were applied once a day to one half-face by the volunteers for 14 consecutive days. Clinical signs (erythema, desquamation, papules, vesicles, edema) and subjective symptoms (tightness, pruritus, burning) were evaluated and scored daily except on weekends. Results: Adapalene 0.1% gel was better tolerated than tretinoin 0.025% gel. The overall mean score calculated from all features combined was significantly higher with tretinoin gel than with adapalene gel (p = 0.002). Conclusion: Adapalene 0.1% gel was significantly less irritating than tretinoin 0.025% gel when tested in acne patients.