Topical therapies, in many cases over-the-counter (OTC) formulations, are available for the treatment of acne, including benzoyl peroxide (BPO), salicylic acid, and retinoids. While these agents provide therapeutic efficacy, combination regimens can offer improved outcomes due to their ability to address multiple pathways involved in acne formation, making them better suited to address the multiple factors involved in acne pathogenesis and the breadth of complexion issues associated with the condition. The present study assessed the efficacy and tolerability of a daily regimen comprised of topical low-dose (2.5%) BPO applied in the morning and topical retinol applied in the evening in 33 subjects with mild to moderate acne who completed the study. A significant reduction in global total acne count from baseline to week 12 (primary endpoint) was achieved, in addition to significant improvements in Investigator Global Assessment (IGA) of acne severity and reductions in inflammatory and non-inflammatory lesions. Treatment also significantly improved acne-complexion graded efficacy parameters (tactile surface roughness, uneven skin tone, skin blotchiness, and lack of skin clarity), and was well-tolerated, with no statistically significant (P<0.05) increases in objective or subjective facial irritation. Significant improvements from baseline to week 12 were observed for both self-assessment of facial skin conditions and quality of life (QoL) scores. No product-related adverse events (AEs) were observed in the study subjects. J Drugs Dermatol. 2022;21(12):1340-1346. doi:10.36849/JDD.6845.