We studied tumor necrosis factor (TNF), lymphotoxin-alpha (LT-alpha), and TNF receptors type 1 (TNFR-1) and type 2 (TNFR-2) gene polymorphisms as well as HLA class II DRB1 alleles in Japanese patients with human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy (HAM) (n = 51), patients with adult T-cell leukemia/lymphoma (ATL) (n = 48), asymptomatic HTLV-I carriers (n = 50), and HTLV-I seronegative, normal controls (n = 112). There were significant differences between HAM patients and normal controls in the distributions of TNF promoter region polymophism at position --857, the LT-alpha gene NcoI polymorphism, and the T-G substitution in exon 6 of the TNFR-2 gene. The distribution of the NcoI polymorphism of the LT-alpha gene was also significantly different between HAM patients and asymptomatic HTLV-I carriers. In contrast, we failed to detect any difference in the frequency of DRB1, TNF promoter at position --1031, --863, or the TNFR-1 promoter --383 polymorphism. The results suggest that the TNF/LT-alpha gene region within the HLA class III of chromosome 6 and the TNFR-2 gene region located on chromosome 1p36 might contribute to susceptibility to HAM, and that aberrant expression or function of these cytokines and the receptor could be involved in the development of HAM.