Adding topical benzoyl peroxide (BPO) to antibiotics can reduce resistant Propionibacterium acnes in patients with acne receiving antibiotic therapy. Benzoyl peroxide often is formulated as a wash, but no published data exist regarding BPO wash formulation efficacy in reducing resistant strains of P acnes. This 3-week, open-label, single-center study evaluated the effects of BPO cleanser 6% on antibiotic-resistant P acnes populations. The study involved 30 healthy adults who were free of acne but had high facial P acnes populations (10,000 colonies/cm2 or more) resistant to erythromycin and tetracycline at 8 microg/mL or more and 2 microg/mL or more, respectively. Participants applied BPO cleanser 6% once daily. Quantitative P acnes cultures were obtained at baseline and weekly for 3 weeks. At baseline, resistance to erythromycin, tetracycline, doxycycline, minocycline, and clindamycin was present in 100% (30/30), 97% (29/30), 83% (25/30), 63% (19/30), and 100% (25/25) of participants, respectively, high-level resistance for erythromycin and tetracyclines and intermediate to high resistance for clindamycin was present in 100% (30/30), 50% (15/30), 33% (10/30), 27% (8/30), and 52% (13/25) of participants, respectively. Total P acnes counts and counts of each resistant strain decreased by approximately 1 log after 1 week of treatment, by at least 1.5 log after 2 weeks of treatment, and by at least 2 log after 3 weeks of treatment, with no differences between resistant and susceptible strains or between highly resistant and low-level resistant strains. Benzoyl peroxide cleanser 6% effectively reduced resistant P acnes populations and offers a useful therapy for controlling antibiotic resistance in patients receiving antibiotics.