Background: The use of topical therapy is a key component in the management of almost all psoriasis patients. Topicals are considered first-line therapy for mild disease and are having an increasing role in moderate or severe psoriasis as an integral part of combination therapy. Halobetasol has been shown be effective in moderate or severe localized plaque psoriasis, and tazarotene affords important effects on epidermal hyperproliferation that may be important in more severe disease. Objective: To investigate the efficacy, safety and tolerability of a once-daily application of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) lotion in comparison with its vehicle in patients with severe localized plaque psoriasis (as defined by an Investigator Global Assessment (IGA) of 4 and Body Surface Area (BSA) of 3%-12%. Methods: Post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies. Sixty-two patients with severe localized psoriasis (mean BSA 7.4) randomized (2:1) to receive HP/TAZ lotion or vehicle, once-daily for 8 weeks, with a 4-week posttreatment follow-up. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score and a score of ‘clear’ or ‘almost clear’), impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion, BSA, reduction in mean baseline IGAxBSA and achievement of a clinically meaningful response (number of patients who achieved at least a 75% improvement in IGAxBSA). Safety and treatment emergent adverse events (TEAEs) were evaluated throughout. Results: By week 8, 34.8% of patients were treatment successes compared with 0.0% on vehicle (P=0.004). HP/TAZ lotion was also significantly superior in reducing psoriasis signs and symptoms and improving BSA. At week 8, 47.4% (erythema), 66.4% (plaque elevation), and 65.4% (scaling) subjects achieved at least a 2-grade improvement, compared with 14.0% (P=0.016), 14.8% (P<0.001) and 14.7% (P<0.001) respectively with vehicle. Patients treated with HP/TAZ lotion achieved a 32.8% reduction in baseline mean BSA, compared with a 39.6% increase with vehicle (P=0.013). HP/TAZ lotion achieved a statistically significant superior reduction in mean IGAxBSA compared to vehicle from week 2 (P<0.001 versus vehicle). By week 8, almost half of the patients treated with HP/TAZ lotion achieved a clinically meaningful response (IGAxBSA-75) and a 52.9% reduction in mean IGAxBSA score compared with a 17.5% increase in those patients treated with vehicle (P<0.001). One patient (2.6%) treated with HP/TAZ lotion discontinued due to AE. Most frequently reported treatment related AEs were application site pain (7.9%), contact dermatitis (5.3%) and pruritus (5.3%). Conclusions: HP/TAZ lotion provides significantly greater efficacy than vehicle that is both rapid and sustained, in patients with severe localized plaque psoriasis, with good tolerability and safety over 8 weeks’ once-daily use. J Drugs Dermatol. 2019;18(10):1012-1018.