MY-24 is an aristeromycin derivative previously shown to protect AG129 type I and II interferon receptor knockout mice from lethal challenge with Tacaribe virus (TCRV). TCRV is nonpathogenic to humans, but is closely related to the highly pathogenic New World arenaviruses that cause often-fatal viral hemorrhagic fever syndromes. Remarkably, MY-24 prevented mortality without reducing TCRV burden in the circulation or tissues. To investigate the mechanism by which MY-24 protects AG129 mice against TCRV infection, we first characterized the natural history of disease in the model with an emphasis on cytokine responses and vascular integrity to establish the best times to evaluate the effects of MY-24 treatment on host responses believed to contribute to pathogenesis and fatal outcome. We found that viral replication in the blood and in various tissues precedes a hyperproduction of proinflammatory mediators that may lead to the destabilization of the endothelial barrier and increased vascular leakage believed to contribute to terminal shock associated with severe cases of hemorrhagic fever. We also found slightly reduced virus titers in certain tissues from MY-24-treated mice, suggesting that there may be a weak antiviral effect; however, TCRV was not cleared from lung, spleen, brain or kidney in recovering animals out to 40 days post-infection, indicative of the establishment of chronic infection in mice that are able to survive the initial challenge. Neutralizing antibodies do not appear to play a major role in the antiviral effect of MY-24, whereas reductions in several key proinflammatory cytokines in mice treated with MY-24 may serve to reduce vascular leakage caused by TCRV infection.