To analyze mechanisms of virulence in the California serogroup bunyaviruses, the virulent La Crosse/original (LAC/original) strain was compared with the avirulent Tahyna/181-57 strain. In suckling mice, both viruses were lethal upon intracerebral injection but differed markedly in their neuroinvasiveness following subcutaneous injection; 20 and 20,000 plaque-forming units, respectively, were equivalent to 1 subcutaneous LD50. The sequential course of infection was followed after subcutaneous injection of 700 plaque-forming units; LAC/original replicated in striated muscle, caused a high titer plasma viremia, invaded the central nervous system, and killed all mice; the same dose of avirulent Tahyna/181-57 failed to replicate in extraneural tissues, did not invade the central nervous system, and caused no apparent illness. Immunofluorescent examination of peripheral and central nervous system tissues showed the same distinctions between virulent and avirulent viruses and pinpointed striated muscle as the major extraneural target of virulent LAC/original virus. Paradoxically, after intracerebral injection of suckling or adult mice, Tahyna/181-57 virus killed more quickly than LAC/original. This difference was correlated with replication differences; Tahyna/181-57 multiplied marginally faster in the brain than did LAC/original virus.