A small population of human T-cell leukemia virus Type I (HTLV-I) carriers develop adult T-cell leukemia after a long incubation period. The results of a series of experiments using animal models suggest that insufficiency of HTLV-I-specific T-cell response induced by vertical HTLV-I infection allows enlargement of the HTLV-I-infected cell reservoir in vivo, a crucial risk factor of adult T-cell leukemia. In this review it is proposed that prophylactic Tax-targeted vaccines for the high-risk group of adult T-cell leukemia, which is characterized by low HTLV-I-specific T-cell response and high proviral load, can reduce the risk. Immunological studies on adult T-cell leukemia patients after hematopoietic stem cell transplantation also suggest that Tax-targeted immunotherapy may be effective against full-blown disease, although its indication may be limited.