The treatment of rabies-infected cynomolgus monkeys (Macaca fascicularis) with human interferon after exposure was studied. The monkeys were infected with rabies street virus by the intramuscular route; larger than or equal to 24 hr after infection, human interferon was administered intramuscularly or by lumbar spinal injection into the cerebrospinal fluid. Whereas 90% of the infected untreated monkeys died, 40%-80% of animals treated with interferon survived. No or only low levels of neutralizing antibody to rabies virus were found in the sera of monkeys that survived after a single intramuscular injection of human interferon. Distinctly higher antibody titers, however, were detected in the sera of surviving monkeys that had been given six consecutive intralumbar doses of interferon beginning three days after infections. Therefore, we conclude that in these monkeys rabies virus propagated until it spread into the central nervous system, where further viral replication was inhibited by the human interferon administered by the intralumbar route.