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Introduction: Efficacy of upadacitinib has been assessed in trials including Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 assessed efficacy of upadacitinib 30 mg and upadacitinib 15 mg against placebo, while Heads Up assessed efficacy of upadacitinib 30 mg in a head-to-head trial against dupilumab 300 mg. A head-to-head trial of upadacitinib 15 mg against dupilumab 300 mg has not been conducted. Network meta-analysis has shown that upadacitinib 30 mg and upadacitinib 15 mg are among the most efficacious targeted systemic therapies, but prior indirect comparisons have not evaluated more stringent outcomes., Methods: A population-adjusted indirect comparison was conducted using post hoc individual patient data from Measure Up 1 and 2 and Heads Up to estimate how upadacitinib 15 mg would have performed if included in Heads Up by adjusting for patient-level covariates. Absolute response rates at weeks 4, 16, and 24 were estimated for the following outcomes: no/minimal itch [Worst Pruritus Numerical Rating Scale (WP-NRS) score of 0/1], Eczema Area and Severity Index (EASI) score of ≤ 3 (EASI ≤ 3), 100% improvement in EASI (EASI 100), both ≥ 90% improvement in EASI (EASI 90) and WP-NRS 0/1, both EASI ≤ 3 and WP-NRS 0/1, and both EASI 100 and WP-NRS 0/1. The analysis was conducted on adult patients, aligned with the intention-to treat population for the clinical trials, and used non-responder imputation., Results: Across all outcomes assessed, the estimated absolute response rates were greatest for upadacitinib 30 mg, followed by upadacitinib 15 mg and then dupilumab. This pattern was observed at week 4, week 16, and week 24., Conclusions: For adults with moderate-to-severe AD, upadacitinib 30 mg appears to be the most efficacious treatment in attaining more stringent and composite outcomes across multiple timepoints, followed by upadacitinib 15 mg and then dupilumab 300 mg., (© 2024. The Author(s).)