The role of autoimmunity in atopic dermatitis (AD) is unclear. We sought to critically examine the occurrence, correlation with severity, and possible causative role of autoreactivity in patients with AD. Our systematic review of studies identified from MEDLINE included 31 experiments that described autoreactivity in patients with AD. We defined autoreactivity as in vitro or in vivo evidence of immune response to autologous human, generic human, or recombinant human proteins or other tissue/cellular components. Autoreactivity prevalence in patients with AD ranged from 23% to 91% in 14 studies involving 2644 participants, although it did not appear to vary with age, sex, or disease duration. In contrast to studies of AD, IgE autoreactivity was not found in healthy subjects or in those with allergic rhinoconjunctivitis, psoriasis, systemic lupus erythematosus, or other inflammatory diseases (8 studies of 816 participants). Two reports found a positive correlation between autoreactivity and AD severity. We suggest that autoreactivity might be playing a causative role in AD based on the magnitude and specificity of the associations found; plausible mechanisms through IgE autoantibodies, IgG autoantibodies, and T_H1 autoreactivity; and experimental elicitation of eczematous lesions after provocation. Whether autoantibodies contribute to AD chronicity now needs to be examined in longitudinal studies.