Systemic immunosuppressive agents are recommended for patients with atopic eczema in whom disease activity cannot be controlled adequately with topical treatments. Guidelines do not give clear advice which agents to prefer. We systematically reviewed clinical trials on systemic treatment for severe atopic eczema to provide evidence-based treatment recommendations. Standardized literature search, independent standardized assessment of eligibility and data abstraction was performed by 2 reviewers. Twenty-seven studies totalling 979 patients were included. Eleven studies consistently showed effectiveness of cyclosporine. Cyclosporine is recommended as first option for patients with atopic eczema refractory to conventional treatment. Evidence from randomized controlled trials also exists for interferon-γ and azathioprine. Although frequently used in clinical practice, systemic glucocorticosteroids have not been assessed adequately in studies. Mycophenolate mofetile showed effectiveness in 2 small uncontrolled studies. Intravenous immunoglobulins and infliximab are not recommended based on published data.