Administration of liposome-encapsulated ribavirin to mice led to ribavirin concentrations in the liver, the primary site of Rift Valley fever virus proliferation, that were fivefold greater than those attained with the same doses of free ribavirin. Liposomal ribavirin given at a dose of either 25 or 50 mg of drug per kg of body weight protected mice against a rapidly lethal high-titer challenge with Rift Valley fever virus, whereas similar doses of free drug or empty liposomes had no detectable benefit. Hence, tissue targeting of ribavirin with liposomes substantially increased the therapeutic index by increasing the efficacy of the treatment. By using liposomes as drug carriers, a nontoxic, low-dose regimen of ribavirin had a therapeutic effect that was comparable to that achieved with higher but potentially more toxic doses of free ribavirin.