Background: Fixed combinations are commonplace in dermatology, providing significant efficacy and tolerability benefits. In some cases, two active ingredients complement each other providing a cumulative or additive effect. In rarer cases, a synergistic effect may be seen where the sum of the two active ingredients combined action is greater than the sum of the efficacy of the constituent parts. Objective: To determine whether a novel halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic effect in the treatment of moderate-to-severe plaque psoriasis. Methods: Post hoc analysis of 212 patients with moderate-to-severe plaque psoriasis randomized (2:2:2:1) to HP/TAZ lotion, HP, TAZ or vehicle once-daily for 8 weeks, with a 4-week posttreatment follow-up. Treatment success was evaluated based on two outcomes: percent of patients achieving at least a 2-grade improvement in Investigator Global Assessment (IGA) and IGA score equating to ‘clear’ or ‘almost clear’; and percent change from baseline in the IGAxbody surface area (BSA) score, an alternative to assessing response to therapy that is more sensitive to area change than the Psoriasis Area Severity Index (PASI). In addition, a clinically meaningful outcome was reported in patients who achieved a 75% reduction in IGAxBSA. Synergy was established when the benefit of combination HP/TAZ lotion was greater than benefit of HP plus TAZ, with a ratio (HP/TAZ divided by HP+TAZ) >1.0. Results: HP/TAZ lotion was synergistic at week 8, and four weeks posttreatment. At week 8, treatment success with HP/TAZ lotion relative to vehicle was 42.8% compared with 32.5% for HP plus TAZ (ratio 1.3); and percent change from baseline in IGAxBSA score relative to vehicle was 51.6% compared with 40.6% for HP plus TAZ (ratio 1.3). At week 12, treatment success with HP/TAZ lotion relative to vehicle was 31.3% compared with 20.0% for HP plus TAZ (ratio 1.6). Percent change from baseline in IGAxBSA score relative to vehicle was 47.3% compared with 34.2% for HP plus TAZ (ratio 1.4). HP/TAZ lotion also provided synergistic benefits in terms of achieving a clinically meaningful outcome, with a ratio of 1.3 and 2.0 at weeks 8 and 12. Conclusions: Halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) fixed combination lotion provides a synergistic benefit in the treatment of moderate-to-severe plaque psoriasis. In addition, by combining two agents into one once-daily formulation, this novel formulation reduces the number of product applications and may help patient adherence. J Drugs Dermatol. 2019;18(3):279-284.