Modoc virus (MODV) is a flavivirus that was first isolated from deer mice (Peromyscus maniculatus) in Modoc County, California during a 1958 surveillance study for novel viruses. Although many flaviviruses are arthropod-borne, MODV has no known intermediate. Subsequent to its initial isolation, MODV was detected in deer mice found in other regions of the United States, including northeastern Colorado. These findings suggested that deer mice may be a reservoir host of MODV. We intramuscularly inoculated 18 deer mice with 105 TCID50 of MODV strain J. Rovnak, Randall 128 J. Cohrs / New Horizons in Translational Medicine 2 (2015) 126–135 M544 for susceptibility testing. Groups of three deer mice were euthanized for necropsy and tissue collection on days 2, 4, 7, 11, 21, and 31. No conspicuous signs of disease occurred in the deer mice; however, minor pulmonary multifocal vasculitis and hemorrhages, multifocal portal hepatitis and splenic lymphoid hyperplasia with hemosiderosis were detected in several deer mice. No virus was detected in sera, suggesting viremia did not occur. Neutralizing antibody was detected as early as day 7-post inoculation, and thereafter all deer were seropositive. MODV RNA was detected by PCR in organs of deer mice euthanized between days 2 and 4, with lung tissue of one deer mouse euthanized on day 7 also indicating the presence of MODV RNA. Viral RNA was detected in most spleens but less frequently in the kidneys and hearts. These data indicate deer mice are susceptible to MODV without signs of disease, although mild pathology occurs in some organs. Clearance of the virus is suggested by the PCR results since no virus was detected in any organ tissue beyond 7 days, which is contrary to the expectation of a natural reservoir host.