Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti‐inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open‐label, 2‐cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream. Tapinarof was systemically absorbed, and measurable amounts were detected in both cohorts. Generally, plasma exposure was greater with the 2% cream and decreased from day 1 to day 21. Median T_max ranged from 1 to 4 hours. Preliminary efficacy results were similar between the 1% and 2% concentrations, with the 1% cream showing better tolerability based on 3 subjects in the 2% cohort who discontinued treatment because of systemic AEs. The efficacy and safety of 1% tapinarof support results of previous positive studies that used a different formulation. However, conclusions in the present study are limited because of the open‐label design and small number of participants. The 1% cream was selected as the concentration for use in future studies because of its lower AE incidence and efficacy comparable to the 2% cream.