Importance ICP-332 is a tyrosine kinase 2 inhibitor currently under investigation for the treatment of atopic dermatitis (AD). Objective To evaluate the safety and efficacy of ICP-332 for moderate to severe AD. Design, Setting, and Participants This double-blind, placebo-controlled, phase 2 randomized clinical trial was conducted between February 6 and November 7, 2023, across 19 centers in China. Individuals aged 18 to 75 years who had diagnosis of AD for 1 year or longer and a history of contraindication or inadequate response to topical therapies were included. Intervention Participants were randomized 1:1:1 to receive ICP-332 at 80 mg or 120 mg, or placebo orally once daily for 4 weeks. Study participants and personnel were blinded to group assignment. Main Outcomes and Measures The primary outcome was safety. The key efficacy outcome was the percentage change from baseline in Eczema Area and Severity Index (EASI) at week 4. Other outcomes included percentages of patients achieving EASI-75 (a ≥75% improvement in EASI) and Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or more points improvement. Results This study included 75 patients (mean [SD] age, 37.3 [18.0] years in the ICP-332 groups and 44.5 [17.4] years in the placebo group; 21 women [28%] and 54 men [72%]). Among the 74 patients included in the safety set, 17 of 25 (68%) in the placebo group, 19 of 25 (76%) in the 80-mg ICP-332 group, and 18 of 24 (75%) in the 120-mg ICP-332 group experienced treatment-emergent adverse events, with all events being mild or moderate. The most common adverse event was decreased blood fibrinogen (1 of 25 [4%] in the placebo group, 6 of 25 [44%] in the 80-mg ICP-332 group, and 5 of 24 [21%] in the 120-mg ICP-332 group). Percentage reductions in EASI at week 4 were −78.2% (95% CI, −89.8% to −66.6%) in the 80-mg ICP-332 group, −72.5% (95% CI, −84.3% to −60.7%) in the 120-mg ICP-332 group, and −16.7% (95% CI, −28.7% to −4.6%) for those receiving placebo. Mean differences vs placebo for percentage reductions from baseline at week 4 in EASI were −61.6% (95% CI, −78.4% to −44.7%; P &lt; .001) and −55.8% (95% CI, −72.8% to −38.9%; P &lt; .001) for 80-mg ICP-332 and 120-mg ICP-332, respectively. There was a statistically significant higher EASI-75 response rate with both ICP-332 doses (64.0% for each; difference vs placebo, 56.0%; 95% CI, 34.4%-77.6%; P &lt; .001) than with placebo and a greater percentage of Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 and improvement of 2 or more points at week 4 in the 80-mg ICP-332 group vs placebo (36.0%; difference vs placebo, 32.0%; 95% CI, 11.7%-52.3%; P = .005). Conclusions and Relevance In this phase 2 randomized clinical trial, ICP-332 demonstrated a favorable safety profile and encouraging efficacy, supporting further development for AD. Trial Registration ClinicalTrials.gov Identifier: NCT05702268