Objective: Investigate the effect of fixed-combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam on target lesion severity in plaque psoriasis. Design: Post-hoc analysis was conducted on data from a Phase 3, randomized, double-blind, multicenter clinical study of Cal/BD foam in the treatment of psoriasis vulgaris for 4 weeks (PSO-FAST; NCT01866163). Participants: In PSO-FAST, 426 patients (≥18 years) with psoriasis vulgaris (≥mild severity) were randomized 3:1 to Cal/BD foam (n=323) or vehicle foam (n=103), applied once daily. Measurements: Assessments included (1) target lesion severity (redness, scaliness, and thickness) at baseline and weeks 1, 2, and 4; and (2) the proportion of patients with ≥50% reduction in total sign score (TSS-50) from baseline at weeks 1, 2, and 4. Results: A greater proportion of patients achieved considerable improvement (a score of 0 or 1) in the severity of target lesions after 4 weeks of treatment with Cal/BD foam vs vehicle foam at week 4 (redness: 76.2% vs 21.4%; P<.001; scaliness: 91.3% vs 61.2%; P<.001; and thickness: 83.3% vs 35.0%; P<.001, respectively). Rapid onset of efficacy was observed as early as week 1. Significantly more patients also achieved TSS-50 at week 4 with Cal/BD foam vs vehicle foam for their target lesions regardless of treatment area, including the elbows and knees (P<.05 for all). Conclusions: Significant improvements in target lesion severity were achieved with up to 4 weeks of treatment with once-daily Cal/BD foam for adults with plaque psoriasis versus vehicle foam, with rapid onset of efficacy observed at week 1. J Drugs Dermatol. 2020;19(2)121-126. doi:10.36849/JDD.2020.4750