Abstract: Background　Abrocitinib is the first approved, highly selective JAK1 inhibitor. By inhibiting JAK1 and reducing the production of inflammatory cytokines, it can effectively alleviate the symptoms of atopic dermatitis (AD). Existing studies have shown that its effectiveness in combination with other topical medications is superior to monotherapy.Objective　To compare the effectiveness and safety of JAK1 inhibitors alone and in combination with PDE4 inhibitors in the treatment of patients with moderate to severe AD. Methods　A prospective, randomized controlled clinical trial design was adopted. Patients with moderate to severe AD who were seen at the Dermatology Outpatient Clinic of the China-Japan Friendship Hospital from November 2023 to March 2024 were selected. Patients were randomly assigned to either the combination therapy group or the monotherapy group. The combination therapy group received oral abrocitinib tablets (a JAK1 inhibitor) at a dose of 100 mg once daily, along with topical crisaborole ointment (a PDE4 inhibitor) applied twice daily. The monotherapy group received only oral abrocitinib tablets at 100 mg once daily. The primary endpoints were the proportion of patients who achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI-75) and/or an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) at week 12. Secondary endpoints included the proportions of patients achieving at least a 50% or 90% improvement in EASI (EASI-50/EASI-90) at weeks 2, 4, 8, and 12, as well as the proportion of patients with a Peak Pruritus Numerical Rating Scale (PP-NRS) score of 4 or higher. Results　A total of 50 patients were enrolled in this study, of whom 10 were lost to follow-up; therefore, 40 patients were included in the analysis, with 19 in the combination therapy group and 21 in the monotherapy group. There were no significant differences in gender, age, or disease duration between the combination group and monotherapy group (P＞0.05). EASI and IGA scores significantly improved compared to baseline in both groups at the 2nd, 4th, 8th, and 12th week follow-up (P＜0.05). At week 12, the EASI-75 response rate was higher in the combination group than that in the monotherapy group (84.21% vs 52.38%, P=0.039). The IGA0/1 response rate was higher in the combination group than that in the monotherapy group (68.42% vs 33.33%, P=0.014). The PP-NRS-4 response rate was higher in the combination group than that in the monotherapy group (73.68% vs 33.33%, P＜0.05). No unexpected serious adverse events were observed. Conclusion　Abrocitinib tablets combined with crisaborole ointment show significant effectiveness in improving the symptoms of AD, and this combined treatment regimen is expected to become a better treatment option for patients with moderate to severe atopic dermatitis.