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Background: Acne treatment can take weeks to deliver noticeable improvements, which may diminish patients' perception of treatment effectiveness and undermine treatment adherence. Combination topical treatments that target multiple acne pathophysiological pathways are more efficacious than topical monotherapies, and simplifying combination treatment by delivering multiple active ingredients as fixed combinations may improve adherence., Methods: This review provides an overview of efficacy with 4 weeks of treatment in pivotal trials of fixed-combination topical treatments for acne. Outcomes assessed were reductions from baseline in inflammatory (IL) and noninflammatory lesions (NIL) and treatment success (≥2-grade reduction in global acne severity score and clear/almost clear skin)., Results: Data were compiled for 7 acne topicals, comprising fixed combinations of adapalene (ADAP), benzoyl peroxide (BPO), clindamycin phosphate (CLIN), and tretinoin (TRET). At week 4, lesion reductions from baseline ranged from 32 to 54% (IL) and 25 to 45% (NIL), while rates of treatment success ranged from 3 to 12%. Overall, efficacy was greatest with triple-combination CLIN 1.2%/ADAP 0.15%/BPO 3.1% gel (IL: 54-55%; NIL: 43-45%; treatment success: 8-12%), followed by combinations of ADAP/BPO (IL: ~42-48%; NIL: ~38%; treatment success: 4-~7%)., Conclusions: In clinical trials of topical fixed-combination formulations, triple-combination CLIN 1.2%/ADAP 0.15%/BPO 3.1% gel yielded greater lesion reductions and rates of treatment success after 4 weeks of treatment than dyad combinations. Even greater differences may be expected with real-world world use, as early improvements may bolster treatment adherence and long-term outcomes. J Drugs Dermatol. 2025;24(1):79-87. doi:10.36849/JDD.8712.