Congenital ichthyosiform erythroderma (CIE) and classic lamellar ichthyosis (LI) are autosomal recessive disorders of cornification (DOC), distinguished previously by clinical, histologic, ultrastructural, and cell kinetic criteria. whether there is further heterogeneity within the CIE group is uncertain. To address the issue of genetic heterogeneity, and to study the pathogenesis of these DOC, skin biopsies from eight CIE, three LI, and six normal subjects were assessed by electron microscopy, including ruthenium tetroxide post-fixation with optical diffraction, to visualize and quantitate intercellular membrane domains. We found abnormal lamellar bodies in CIE and distinctive alterations in intercellular lamellar bilayer architecture among patients with CIE and three patients with LI. Two biopsies from two patients at different sites demonstrated the consistency of these findings. Moreover, in both CIE and the three LI patients, desmosomes persisted throughout the outer layers of the SC, indicative of impaired degradation. Our ultrastructural observations support the previously reported phenotypic distinction between CIE and LI, and the further likelihood of genetic heterogeneity within CIE. However, these studies do not support the division of the autosomal recessive ichthyoses into three subgroups based upon cytosolic structural abnormalities. Finally, these studies provide new insights into the pathogenesis of the autosomal recessive DOC.