<h3>Importance</h3> Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. <h3>Objective</h3> To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. <h3>Data Sources</h3> The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. <h3>Study Selection</h3> English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. <h3>Data Extraction and Synthesis</h3> Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. <h3>Main Outcomes and Measures</h3> Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. <h3>Results</h3> A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, −1.1; 95% CrI, −1.7 to −0.5 [low certainty]) and dupilumab (standardized mean difference, −0.9; 95% CrI, −1.0 to −0.8 [high certainty...