Combination acne medications provide enhanced treatment opportunities. A commonly used acne therapy may combine a topical antibiotic with benzoyl peroxide (BPO) to prevent antibiotic resistance while optimizing control of microcomedone formation with a retinoid. Unfortunately, this combination of highly efficacious medications may cause irritation because of the inherent skin irritancy of BPO and retinoids. The present study was undertaken to determine if vehicle optimization of a clindamycin-BPO formulation could increase the tolerability of an added retinoid. Forty-six women with mild to moderate facial acne were enrolled in a 3-center, institutional review board-approved, 2-week, split-face study to compare an optimized vehicle (glycerin and dimethicone) clindamycin-BPO formulation with a traditional clindamycin-BPO formulation, with tretinoin cream 0.025% applied to the entire face. The use of the optimized vehicle clindamycin-BPO formulation in combination with tretinoin cream 0.025% resulted in significantly less erythema and dryness on evaluation days 4, 7, and 14 (P < .05), as assessed by the blinded dermatologist investigators. The incorporation of new vehicles into topical dermatologic medications allows medication combinations with enhanced tolerability.