We attempted to protect three rhesus monkeys from Lassa fever by vaccination with a preparation of purified whole Lassa virus which had been inactivated by gamma irradiation. The vaccinated monkeys developed antibodies against the three major viral proteins of Lassa virus demonstrated by radioimmunoprecipitation. When the three vaccinated monkeys and two unvaccinated control monkeys were challenged all five became severely ill and died. Prior to death a secondary, high-titer antibody response to Lassa virus was observed in the three vaccinated monkeys, whereas the two unvaccinated monkeys developed a primary, low-titer antibody response. Though titers of Lassa virus in serum reached peak levels earlier following challenge in the non vaccinated, at the time of death serum and organ virus titers did not differ significantly. Changes in platelet aggregation, leukocyte counts, and liver enzymes, abnormalities of which have been associated with severity of Lassa fever, were found to be comparable in the two groups. The humoral antibody response measured in these animals following vaccination, although of the same magnitude as found in humans recovered from Lassa fever, was insufficient to protect the animals from this fatal disease. Evidence is now accumulating that the cell-mediated immune response must be activated in order to protect against challenge with arenaviruses.