Benzoyl peroxide (BPO) is highly effective against acne and a mainstay of acne treatment. It also has the potential to irritate the skin, a risk that is generally considered dose dependent. Because compliance is poor with skin products found to be irritating, there is a need for gentle BPO products. Microsponge formulations which provide a gradual release of the active ingredient over time and thus may be less irritating could be a potential solution to this problem. The purpose of this study was to assess the irritancy of a prescription BPO wash 7% with microsponge delivery system relative to 3 other prescription washes—branded BPO creamy wash 4%, generic BPO creamy wash 4%, and BPO foaming cloths 3%—and 1 over-the-counter (OTC) product, OTC branded BPO wash 2.5%, as well as a negative control (no product) using a standard 21-day patch test protocol. Thirty-two participants were enrolled. Branded BPO creamy wash 4% was found to be the most irritating of the washes tested. Benzoyl peroxide wash 7% with microsponge delivery system—the prescription wash with the highest BPO concentration—and OTC branded BPO wash 2.5% were proven the least irritating. This study suggests that microsponge technology is effective in reducing the skin irritation associated with BPO.