The aim of this study was to compare the efficacies of systemic treatments with dupilumab, tralokinumab and Janus kinase inhibitors for moderate-to-severe atopic dermatitis. A systematic review following Pre-ferred Reporting Items for Systemic Reviews and Me-ta-Analyses (PRISMA) guidelines was performed using Medline, EMBASE and Cochrane library. All randomized controlled trials investigating the efficacy of systemic treatments for moderate-to-severe atopic dermatitis in adults were included. Primary outcomes were the proportion of patients with atopic dermatitis achieving 50%, 75%, and 90% improvement in Eczema Area and Severity Index (EASI) score after dupilumab, tralo-kinumab or Janus kinase inhibitors. Nineteen studies totalling 6,444 patients were included. In monotherapy studies, upadacitinib 30 mg once daily had the numeri-cally highest efficacy regarding EASI-50, EASI-75 and EASI-90. In combination therapy studies with topical corticosteroids, dupilumab 300 mg once every other week had highest efficacy regarding EASI-50, and ab-rocitinib 200 mg once daily had the highest score regarding EASI-75 and EASI-90. Analysis provided evidence that dupilumab, tralokinumab and Janus kinase inhibitors all had an acceptable efficacy profile and re-sulted in clinically relevant improvements in EASI sco-re. Furthermore, upadacitinib and abrocitinib seem to have great potential to treat patients with atopic der-matitis. However, further studies are needed to determine the long-term efficacy of Janus kinase inhibitors in adults with moderate-to-severe atopic dermatitis.