In contrast to recently reported successful methotrexate therapy of congenital bullous ichthyosiform erythroderma (CBIE), two cases failed to respond to the dosages of methotrexate normally used in psoriasis. Thiamiprine was also without effect. This was despite the demonstration of markedly increased epidermal turnover in these patients using tritiated thymidine autoradiography. We suspect the failure to respond is because the increased epidermal cell turnover in this disease is a secondary phenomenon involving mechanisms not responsive to antimetabolites.