Human T cell lymphotropic virus type I (HTLV-I) is a retrovirus that has been linked to HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), a chronic or inflammatory neurological disease with some resemblance to multiple sclerosis. We used the polymerase chain reaction to amplify viral env genes in foci of inflammation and demyelination in the nervous system to adduce additional evidence of the association of HTLV-I with the neuropathological changes in HAM/TSP, and document in this report such an association. We also sought evidence of a distinct viral species in the lesions by amplifying, cloning and sequencing the env genes from tissues sections in which there were pathological changes. We did not find changes in the env gene that correlated with HTLV-I-associated neurological disease vs adult T cell leukemia or with the nervous system vs peripheral blood and lymphoid organs. We did, however, find evidence of extensive mutation and possibly deletions in the env gene in HTLV-I-associated neurological disease. We interpret these findings of increased genetic diversity as a reflection of higher rates of viral replication in HTLV-I-associated myelopathy that support a model of pathogenesis in which increased viral replication activates immune cells that subsequently enter the nervous system and cause injury by immunopathological mechanisms.