Background: Treatment responses may differ between patients with severe versus moderate atopic dermatitis (AD). Objectives: To assess dupilumab response by baseline AD severity in adolescent and adult patients with moderate-to-severe AD. Methods: We assessed dupilumab response by baseline AD severity in 1719 patients aged ≥12 years with moderate-to-severe AD from five randomized, double-blind, placebo-controlled trials. Patients received subcutaneous placebo or dupilumab as monotherapy (300 mg [adults, adolescents] or 200 mg [adolescents] every 2 weeks; 16 weeks), or with concomitant topical corticosteroids (TCS) (adults; 16/52 weeks). Patients were stratified by baseline Investigator's Global Assessment (IGA) score (3 [moderate]/4 [severe]). Results: Dupilumab-treated patients with moderate AD had numerically higher absolute proportions of patients achieving IGA 0/1 (clear/almost clear) than those with severe AD; risk differences (dupilumab vs. placebo) were 18.9–35.5 for moderate AD and 16.4–34.2 for severe AD. For all other endpoints assessed, no meaningful differences or consistent response patterns between moderate and severe subgroups were observed. Conclusions: Dupilumab with or without TCS demonstrated similar efficacy in patients with moderate or severe AD.