Rabies is an acute viral encephalitis that is invariably fatal following the manifestations of clinical signs. To subvert the course of the disease, rabies post-exposure prophylaxis (PEP) is widely utilized. The immunogenicity and efficacy of Fermi-type rabies vaccine produced in Ethiopia was determined in mice subjected to intracranial challenge with rabies virus, and in humans undergoing rabies PEP in Ethiopia. Mice were randomly assigned into 5 groups. Group 1 received 0.25 ml each of phenolized saline intraperitoneally for 14 consecutive days. Mice in groups 2-5 received 0.25 ml of rabies vaccine for human PEP for the same period of time. Blood samples were drawn from the retro-orbital vein of all mice on designated days for the determination of rabies virus neutralizing antibody (VNA) using the mouse serum neutralization test. Mice were subsequently challenged intracranially with rabies virus at a concentration of 64 MICLD50 90 days post initial vaccination. Rabies neutralizing antibody titers in the sera of immunized mice ranged from 4.6 to 25 IU/ml. Booster vaccine doses did not seem to induce significant increases in the immune response of vaccinated mice, all of whom withstood intracranial challenge with rabies virus. Rabies VNA was further determined in 12 patients vaccinated in accordance with the prescribed dosage of Fermi-type vaccine for human rabies PEP. Most had > 0.5 IU/ml of rabies VNA by day 14, and none detectable at day 1. In contrast to mice, booster doses of vaccine may contribute to slightly higher rabies VNA titers in humans but our small sample size, on top of significant defaulter rates in the study participants, limits our interpretation of the effects of booster vaccine doses. The results of this study are the first documentation of the efficacy and immunogenicity of the Ethiopian Fermi type nerve tissue vaccine in both humans and mice.