Background: A new aqueous gel formulation of dapsone has been developed that allows clinically-effective doses of dapsone to be administered topically with minimal systemic absorption. Objectives: The goal of these studies was to evaluate the efficacy and safety of dapsone gel, 5% in the treatment of acne. Methods: Patients 12 years of age and older with acne vulgaris (N = 3010) participated in two identically-designed 12-week, randomized, double-blind studies of twice-daily monotherapy with dapsone gel, 5%, versus a vehicle gel. Results: Dapsone gel-treated patients achieved superior results in terms of the investigator's global acne assessment (P < .001) and the mean percentage reduction in inflammatory, noninflammatory, and total lesion counts (all, P < .001) at week 12. Reductions in inflammatory lesion counts favoring dapsone gel over vehicle were apparent as early as 2 weeks and reached statistical significance by 4 weeks. No clinically significant changes in laboratory parameters, including hemoglobin, even among glucose-6-phosphate dehydrogenase-deficient patients, were observed. Adverse events were comparable between the treatment groups and rarely led to discontinuation. Limitations: Adjunctive topical treatments and their impact on acne were not studied in this trial. Conclusions: Dapsone gel, 5% appears to be an effective, safe, and well-tolerated treatment for acne vulgaris, with a rapid onset of action. © 2007 American Academy of Dermatology, Inc.