BACKGROUND The use of multiple topical drugs for the treatment of acne may cause elevated irritation. Therefore, the selection of a combination regimen should include a careful consideration of the irritation potential of the individual acne medications. OBJECTIVE AND METHODS To compare the cumulative irritation potential of adapalene gel 0.1%, tazarotene cream 0.05%, and tretinoin microsphere 0.04% when applied in combination with two benzoyl peroxide/clindamycin topical gels in 35 healthy subjects in a 3-week, randomized, controlled study. RESULTS The mean cumulative irritancy index of adapalene combinations was significantly lower relative to tretinoin and tazarotene regimens (all P<.01). Test areas exposed to tretinoin or tazarotene were also more likely to be discontinued for severe irritation than those exposed to adapalene. There were no serious adverse events. No significant difference in the irritancy potentials of tazarotene and tretinoin combination regimens was observed. CONCLUSIONS Adapalene gel 0.1% has tolerability superior to both tazarotene cream 0.05% and tretinoin microsphere 0.04% when used in topical combination therapy. In view of the lower irritation potential observed in this study, along with its demonstrated efficacy, adapalene gel 0.1% in combination with antimicrobial agents may be used as part of an aggressive treatment regimen for the management of acne.