Neurotropism of bluetongue virus (BLU) has been demonstrated in the developing brain of fetal ruminants and neonatal mouse models. Two strains of BLU serotype 11, UC8 and UC2, differentiated by their electrophoretic characteristics and abilities to cause brain lesions in bovine fetuses and neonatal mice were investigated to determine differences in tissue distribution in new born mice following subcutaneous inoculation. Tissue analysis by reverse transcriptase-polymerase chain reaction (RT-PCR) showed selective distribution of both BLU strains to the brain and spleen as early as 3 h post-inoculation (PI) but viral RNA was not detected in the blood or other tissues for the duration of the 15 day experiment. UC2 persisted within the brain and spleen until 9 h PI without development of CNS lesions. In contrast, UC8 persisted within the spleen for 24 h and in the brain through the end of the experiment. UC8 infected mice developed necrotizing lesions throughout the cerebrum and cerebellum that were most severe on PI days 11 and 13. Immunohistochemical staining for BLU identified infected cells within the brains of UC8 inoculated mice before inflammatory lesions were present and gave supportive evidence of the ability of UC2 to infect brain cells. Our results show that both UC8 and UC2 selectively target the brain and spleen in neonatal mice early after inoculation and suggest that the differences in neurovirulence between these strains are due to differences in replicative efficacy within host target cells.