Although the mechanism of multiple sclerosis (MS) remains elusive, it is generally hypothesized to be an autoimmune disease targeting the central nervous system (CNS) myelin. Extensive epidemiological and genetic surveys indicate that MS is caused by an interplay between the environment and genetic traits determined by normal polymorphisms in multiple genes. In Japanese, epidemiological surveys gave the prevalence rates of 0.7 to 8.9/100,000. There is a small but significant north-to-south gradient of MS prevalence rates in Japan, suggesting that environmental factors varying with latitude also play a role in developing MS even in the low prevalence areas. Conventional MS in Japanese is, like MS in Caucasians, associated with HLA-DRB1*1501 whereas opticospinal MS is associated with HLA-DPB1*0501. The ratio of conventional to opticospinal MS has increased rapidly in Japanese born after 1960s, suggesting that the modernization occurred after 1960s in Japan has modifying effects on MS susceptibility and phenotypes.