This randomized, investigator-blinded study evaluated the level of skin tolerance to adapalene gel 0.1%, tretinoin cream 0.025%, or tretinoin microsphere gel 0.1% when applied in combination with clindamycin phosphate lotion 1%, erythromycin gel 2%, benzoyl peroxide gel 5%, or erythromycin-benzoyl peroxide gel. A total of 37 subjects underwent daily application of the topical antimicrobial and retinoid products to sites on their upper back under protective patches for approximately 16 hours each day; Friday patches were left in place over the weekend. Testing continued daily for 3 weeks or until discontinuation caused by a severe adverse reaction to any of the test products or to the patch. Adapalene gel 0.1% demonstrated statistically significantly (P < .001) less irritation after repeated application under occlusive conditions than tretinoin cream 0.025% or tretinoin microsphere gel 0.1%. Moreover, the application of adapalene gel 0.1% under these conditions, concomitantly with various antimicrobial agents, was safe and well tolerated in this subject population. In view of its low irritation potential and its efficacy, adapalene gel 0.1%, in combination with antimicrobial agents should be considered for the treatment of acne vulgaris.