We investigated the biochemical and morphologic alteration in skin of amyotrophic lateral sclerosis patients. We found an obvious high expression of leukemia inhibitory factor and distinct epidermal hyperplasia in the skin of amyotrophic lateral sclerosis patients compared with disease controls. The thickness and cell density, as well as the leukemia inhibitory factor immunostain density, of the epidermis in amyotrophic lateral sclerosis patients correlated positively with duration of illness. The striking fact was the significant epidermal hyperplasia correlating with leukemia inhibitory factor expression in amyotrophic lateral sclerosis patients (r = 0.94, p < 0.001). In vitro experiments revealed that leukemia inhibitory factor stimulated keratinocyte proliferation in primary keratinocyte culture and induced epidermal hyperplasia in skin organ culture. These findings lead to the hypothesis that a high expression of leukemia inhibitory factor is closely associated with epidermal hyperplasia in amyotrophic lateral sclerosis patients.