A 3-step acne system has been developed to enhance the bioavailability and follicular penetration of benzoyl peroxide (BPO). Participants with mild to moderate facial acne vulgaris were randomly assigned to 10 weeks' facial treatment with the 3-step acne system (proprietary salicylic acid cleanser 2% twice daily, proprietary salicylic acid toner 2% once daily, and solubilized BPO gel 5% twice daily) or with control cleanser twice daily plus clindamycin 1%-BPO 5% gel (jar formulation) twice daily. Among 139 participants enrolled, the 3-step acne system was at least as effective as clindamycin-BPO in reducing noninflammatory lesion counts in the early weeks of treatment in the absence of an antibiotic (mean reductions were 27% vs 13%, 39% vs 25%, 40% vs 33%, and 42% vs 42% at weeks 2, 4, 6, and 10, respectively) (all not significant). Both regimens were associated with comparable reductions in inflammatory lesion counts at all time points. Both regimens also were generally well-tolerated with mean scores for erythema, dryness, peeling, burning/stinging, and itching less than mild in both groups at all time points. The 3-step acne system is at least as effective as clindamycin-BPO in reducing noninflammatory lesion counts in the early weeks of treatment in the absence of an antibiotic, which is likely attributed to the solubilized BPO formulation.