Methotrexate given orally once each week was used to treat two patients with epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma). Neither objective clinical nor histopathological improvement occurred. These results support the mounting evidence that this hyperplastic dermatosis does not respond to antifolate therapy. Failure to respond to Methotrexate is, perhaps, unexpected on the basis of epidermal biometric data and previous experience with the use of folic acid antagonists in psoriasis; however, it may indicate a different or more complex subcellular disease process. An exact clinical and histological diagnosis and, where possible, epidermal kinetic data should be required before treating an ichthyosiform dermatosis with Methotrexate. Methotrexate may be indicated in the ichthyosiform dermatosis, severe erythrodermic psoriasis, which fails to respond to potentially less dangerous antipsoriatic measures.