Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an “allergic”/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly T H 2/T H 22 polarization, and epidermal barrier defects. We sought to define whether both variants share a common pathogenesis.We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry.A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10 −5 ) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including T H 2) was detected in patients with intrinsic AD, particularly T H 17 and T H 22 cytokines. Positive correlations between T H 17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and T H 2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin).Although differences in T H 17 and T H 22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a T H 2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.