Potent topical corticosteroids (TCSs) are the mainstay of psoriasis treatment. Safety concerns have limited use to 2 to 4 weeks. The objective of our study was to investigate the safety and efficacy of once-daily halobetasol propionate (HP) lotion 0.01% in moderate to severe plaque psoriasis through 2 multicenter, randomized, double-blind, vehicle-controlled phase 3 studies (N=430). Participants were randomized (2:1) to HP lotion 0.01% or vehicle once daily for 8 weeks, followed by 4 weeks of follow-up. The primary efficacy assessment was treatment success (at least a 2-grade improvement in baseline investigator global assessment [IGA] score and a score of 0 [clear] or 1 [almost clear]). Additional assessments included improvement in psoriasis signs and symptoms, body surface area (BSA), and a composite score of IGA×BSA. Safety and treatment-emergent adverse events (AEs) were evaluated throughout. We found that HP lotion 0.01% demonstrated statistically significant superiority over vehicle as early as week 2 and also was superior in reducing psoriasis signs and symptoms and BSA involvement.