Adult C3H/RV mice were highly resistant and adult C3H/He mice were highly susceptible to lethal encephalitis after intraperitoneal inoculation of Banzi virus (flavivirus), but the infectivity of the virus was the same for both strains of mice. Yields of virus were similar from lymphoid tissues of C3H/He and C3H/RV adult mice, but titers of virus in the brain were significantly lower in C3H/RV mice. Lesions of encephalitis developed in both strains but remained mild and self-limiting in C3H/RV mice, whereas widespread necrosis occurred in the brains of C3HI He mice. Resistance to lethal infection after intraperitoneal inoculation developed postnatally in C3H/RV mice and did not reach significant levels until mice were at least four weeks old. Mortality rates among C3H/RV and C3H/He mice were comparable after intracerebral inoculation of virus. Yields of virus, brain lesions, and immunofluorescent staining patterns for viral antigen were similar in intracerebrally inoculated C3H/He and C3H/RV mice. Results indicate that tissues of resistant and susceptible mice in vivo can support replication of Banzi virus about equally well. Thus, genetic resistance to lethal infection with Banzi virus in these strains of mice does not seem to be solely dependent on resistance of tissues to viral replication.