The harlequin ichthyosis (ichq) mouse mutation arose spontaneously in 1989 in a colony of BALB/cJ mice at The Jackson Laboratory. Affected mice developed thick skin due to formation of compact, orthokeratotic scales that fractured over articular surfaces, secondary to bending. Harlequin ichthyosis mice on the inbred BALB/cJ background died between 9 and 12 days of age. Onset of the clinical phenotype corresponded with emergence of hair fibers from follicles at 5 days of age. There was marked proliferation of the root sheaths of anagen hair follicles, limited to the region within the dermis. Sebaceous glands were present but small compared with those of littermate controls. Emerging hair fibers were surrounded by a thick, compact sheath of cornified cells. Mutant skin contained large mitochondria with lamellar-shaped, electron-dense structures at the ultrastructural level. Keratohyalin granules were smaller and less pleomorphic than those in control mice. Lamellar bodies were not evident in either mutant or littermate control mice. Using a panel of antibodies to evaluate changes in keratinocyte differentiation, mouse-specific keratin 6 was overexpressed in the suprabasilar, hyperplastic epidermis. Loricrin expression, within the cytoplasm of cells in the stratum granulosum, decreased rapidly postmortem, unlike that in normal mice where it was stable for over 24 hours postmortem. Filaggrin expression, within granules of cells in the stratum granulosum, was prominent, corresponding to hypergranulosis evident by light microscopy in mutant mouse skin. Skin grafts from harlequin ichthyosis mice grafted onto immunodeficient nude mice maintained the phenotype for the 10-week observation period. The mutant gene locus mapped to the proximal end of mouse chromosome 19 and is inherited as a fully penetrant autosomal recessive gene. The harlequin ichthyosis mouse mutation is very similar to human type 2 harlequin ichthyosis for which it may be a good model.