Adapalene 0.1% gel (Differin gel) is a recently introduced topical treatment for mild to moderate acne which has been demonstrated to be much better tolerated and at least as effective as tretinoin 0.025% gel. We compared the tolerance of adapalene 0.1% gel with six different formulations and concentrations of tretinoin. A total of 55 healthy human subjects were enrolled in two controlled, randomized, observer blinded, intraindividual comparison studies. In the first study, adapalene 0.1% gel was evaluated for its 21-day cumulative irritation potential compared with tretinoin 0.025%, 0.05% and 0.1% cream, tretinoin 0.01% and 0.025% gel, and petrolatum (control). In the second study, adapalene 0.1% gel was evaluated for its 21-day cumulative irritation potential compared with tretinoin 0.025%, 0.05% and 0.1% cream, tretinoin 0.1% gel microsphere, and petrolatum (control). In both studies, cumulative irritation scores helped to define three groups of common irritancy potential, with significant differences between each group. In study A, the three groups were in descending order of irritancy: tretinoin 0.1% cream and tretinoin 0.05% cream; tretinoin 0.025% gel, tretinoin 0.01% gel and tretinoin 0.025% cream; adapalene 0.1% gel and petrolatum (control). In study B, the three groups were in descending order of irritancy: tretinoin 0.1% cream; tretinoin 0.05% cream, tretinoin 0.025% cream and tretinoin 0.1% gel microsphere; adapalene 0.1% gel and petrolatum (control). The experimental results show that adapalene 0.1% gel is significantly better tolerated than any of six formulations of tretinoin, including two gels, three creams and a microsphere formulation, ranging in potency from 0.01% to 0.1%.