HAM/TSP is a chronic inflammatory disease of the spinal cord. It is rather rare in HTLV-1-infected individuals. Immunogenetic factors of the HLA complex have been identified that support or prevent the development of the disease. In HAM/TSP patients a characteristic constellation of high proviral loads and increased cellular and humoral immune responses have been established. Immune dysfunction in HAM/TSP patients might be partly explained by HTLV-1 tax p40 transactivation of cellular genes in infected CD4+ T lymphocytes. The oligoclonal expansion of infected T lymphocytes, the variation of tax p40 within HTLV-1 carriers, and the regulation of proviral gene expression are possible determinants for disease development and need to be clarified in future studies.