Acne vulgaris is a widely prevalent skin disorder primarily treated with retinoids, which have been shown to cause skin irritation. This report describes the combined analysis of 2 similar phase 3 studies designed to evaluate the efficacy and safety of an aqueous gel formulation of tretinoin relative to its vehicle (both studies) and a marketed microsphere formulation of tretinoin (one study) for once-daily topical treatment of acne. Randomized participants 10 years and older with mild to moderate acne (N=1537) received tretinoin gel 0.05% (n=674), tretinoin gel microsphere 0.1% (n=376), or vehicle (n=487) once daily for 12 weeks. Tretinoin gel was more effective than vehicle in reducing inflammatory (P<.001) and noninflammatory (P<.001) lesion counts over 12 weeks. Treatment success rate (global severity score, 0 or 1) was significantly greater in the tretinoin gel 0.05% group compared with the vehicle group (P<.001). The efficacy rate of tretinoin gel 0.05% was approximately 12% less than tretinoin gel microsphere 0.1%. Adverse events (AEs) were generally mild to moderate and rarely resulted in participant discontinuation. Incidence of skin-related AEs in the tretinoin gel 0.05% group (31%) was significantly lower compared with the tretinoin gel microsphere 0.1% group (52%)(P<.001). Thus, tretinoin gel 0.05% applied once daily is a well-tolerated and effective therapy for acne vulgaris and is associated with a low incidence of skin-related AEs.