Abstract Lebrikizumab (LEB) is a high-affinity monoclonal antibody targeting interleukin (IL)-13, preventing IL-13 signalling via the IL-4Rα/IL-13Rα1 receptor complex. Here, we report 16-week efficacy and safety outcomes of LEB monotherapy in patients with moderate-to-severe atopic dermatitis from two 52-week, randomized, double-blinded, placebo-controlled phase III trials, ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). Eligible adults and adolescents (aged 12–17 years, weighing ≥ 40 kg) from ADvocate1 and ADvocate2 were randomized (2 : 1) to subcutaneous LEB 250 mg (500 mg loading dose at baseline and week 2) or placebo every 2 weeks (Q2W). Efficacy analyses included proportions of patients achieving Investigator’s Global Assessment (IGA) 0/1 and Eczema Area and Severity Index (EASI)-75 (coprimary endpoints), EASI-90, and pruritus numeric rating scale (NRS) ≥ 4-point improvement from baseline to week 16. This was a pooled analysis of ADvocate1 and ADvocate2, where IGA 0/1 and EASI-75 and EASI-90 were analysed in 564 and 287 patients (LEB 250 mg and placebo), respectively, and pruritus NRS in 516 and 264 patients, respectively. Cochran–Mantel–Haenszel with Markov chain Monte Carlo multiple imputation was performed. Patients treated with LEB 250 mg and placebo for 16 weeks achieved, respectively, IGA 0/1 response rates of 38.1% (n = 215) and 11.7% (n = 34; P < 0.001); EASI-75 responses of 55.4% (n = 313) and 17.2% (n = 49; P < 0.001); EASI-90 responses of 34.5% (n = 195) and 9.2% (n = 26) (P < 0.001); and pruritus NRS ≥ 4-point improvement responses of 42.9% (n = 221) and 12.2% (n = 32; P < 0.001). The percentage of patients reporting one or more treatment emergent adverse event(s) was lower in the LEB group (49.6%) than in the placebo group (59.0%; P = 0.009). These data suggest that LEB 250 mg Q2W for 16 weeks is an efficacious and safe treatment option for adult and adolescent patients with moderate-to-severe atopic dermatitis. Funding sourcesThis study was funded by Dermira, a wholly owned subsidiary of Eli Lilly and Company. Almirall has licensed the rights to develop and commercialize lebrikizumab for the treatment of dermatology indications, including atopic dermatitis, in Europe. Lilly has exclusive rights for development and commercialization of lebrikizumab in the United States and the rest of world outside Europe.