Technical Abstract: Outbreaks of clinically severe acute Bovine Virus Diarrhea (BVD) have been associated with infections of cattle with BVD virus of genotype 2 (BVDV 2). The objective of this study was to correlate spread of a strain of BVDV 2 to different organ tissues with development of lesions in severe acute BVD. Eight 14-day-old and two 2-month-old colostrum-deprived calves were intranasally inoculated with 106 TCID of BVDV 2 strain 1373. Two 14-day-old calves served as non infected controls. BVDV 2 strain 1373 was an isolate from the widespread outbreak of clinically severe BVD in Ontario, Canada, in 1993. Two calves each were euthanized at days 3, 6, and 12 post inoculation (pi), and one each at days 8, 9, 13 and 14 pi. Representative tissues were collected for immunohistological and histological examination. Inoculated calves developed clinical signs characterized by high fever, decreased numbers of leukocytes and decreased numbers of thrombocytes. Viral antigen was detected focally in lymphoid tissues at day 3 pi. At days 6, 8, 9, 12 and 14 pi viral antigen became increasingly widespread throughout organs and tissue types. Presence of viral antigen in lymphoid tissues was associated with severe depletion of all compartments. Lesions in other tissues were not well correlated with the distribution of viral antigen. In the calf at day 13 pi, depletion of lymphoid tissues was observed, but viral antigen had been cleared from most tissues and was present in vascular walls only.