HTLV-II env protein, which cross-reacts with HTLV-I env, has been known to induce antibodies in infected individuals. In an attempt to suppress HTLV-II infection, we first generated HTLV-II env precursor glycoprotein (gp63) using baculovirus vector and the Sf-9 cell system. The production of antibodies to the cleaved env glycoprotein gp46 was verified by analysis of immunized rabbit sera as well as HTLV-II infected human sera using Western blotting. Moreover, the rabbit antibody was shown to suppress syncytial formation of the cells (Vines) infected with human T-cell leukemia virus type II (HTLV-II: HTLV-II-Vines). HTLV-II infection in rabbits was produced by intravenous injection of HTLV-II-Vines into female rabbits (New Zealand White). Antibody against HTLV-II could be detected by the 2nd week after inoculation, and its titer reached the maximum at the 10th week. Specific antibodies against env gp46 and gag p24 were detected in 2 of 2 rabbits and in 1 of 2 by Western blotting methods, respectively. Proviral DNA was detected by nested PCR, which was verified by Southern hybridization, at all times checked after inoculation, suggesting the persistence of infection, albeit at low levels. In the studies to determine if vaccination could protect against HTLV-II infection, rabbits were first immunized with the env protein, then were challenged by inoculation with HTLV-II-Vines as described above. Employing nested PCR, the provirus could not be detected at any time after challenge. The observation that active immunization could effectively protect rabbits from infection would seem to have important implications for equivalent vaccination of humans against both HTLV-I and HTLV-II.