Background <p>Tapinarof cream 1% is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration to treat atopic dermatitis (AD) in patients down to age 2 years.</p> Objective <p>The aim of this study was to evaluate the safety and pharmacokinetics of tapinarof cream 1% once daily (QD) in adolescents and children with extensive AD under maximal usage conditions.</p> Methods <p>Patients with a validated Investigator Global Assessment scale for Atopic Dermatitis™ (vIGA-AD™) score ≥&#xa0;3 and body surface area (BSA) involvement ≥&#xa0;25% (ages 12–17 years) or ≥&#xa0;35% (ages 2–11 years) were enrolled into three age cohorts (2–6, 7–11, and 12–17 years) and received tapinarof cream 1% QD for 4 weeks.</p> Results <p>Overall, 36 patients (12 per cohort) were enrolled; mean BSA affected was 42.8% (range 26.0–90.0) and mean Eczema Area and Severity Index (EASI) score was 23.8. At baseline, 28 patients (77.8%) had a vIGA-AD™ score of 3 (moderate). No-to-minimal tapinarof systemic exposure was observed (25% of post-treatment plasma samples were below the quantifiable limit of a highly sensitive assay [&lt;&#xa0;50&#xa0;pg/mL]). Mean maximum plasma concentration (<i>C</i>_max) was 2.44&#xa0;ng/mL, and median time to <i>C</i>_max was 2.9&#xa0;h. Eight patients (22.2%) reported treatment-emergent adverse events (TEAEs), which were mild or moderate; only one patient discontinued due to two unrelated TEAEs. One case of mild folliculitis and no contact dermatitis occurred. Tapinarof was well tolerated, including on sensitive skin and extensor/flexural surfaces.</p> Conclusion <p>Tapinarof cream exhibits highly favorable safety and pharmacokinetics in adolescents and children down to age 2 years with extensive AD.</p> Trial Registration <p>ClinicalTrials.gov: NCT05186805.</p>