A devastating outbreak of Severe Acute Bovine Viral Diarrhea in the North American Great Lakes region beginning in the 1990s resulted in economic losses of millions of dollars. This disease has been attributed to what appears to be a newly emerged form of noncytopathic bovine viral diarrhea virus type 2 (ncpBVDV2). Prior to this outbreak, it was believed that only cytopathic BVDV could cause fatal disease. In this study we confirm the virulence of a noncytopathic isolate (24515) from this outbreak, and contrast it to the disease caused by a more typical noncytopathic isolate (11Q) from a clinically normal calf. The high virulence isolate 24515 caused severe morbidity characterized clinically by fever, diarrhea, dehydration, and depression and haematologically by lymphopenia, neutropenia and thrombocytopenia. In contrast, the low virulence isolate 11Q elicited only a mild, almost undetectable disease. Marked differences in histologic lesions between 24515 and 11Q inoculated calves were consistent with differences in viral antigen distribution. While viral antigen and associated microscopic lesions in 11Q inoculated calves were restricted to lymphoid tissues, 24515 viral antigen and associated microscopic lesions were also observed in the upper and lower alimentary tracts. Genomic sequencing revealed a 48 nucleotide insert within the NS2/3 gene of the high virulence 24515 and not in the low virulence 11Q. The 24515 NS2/3 insert contained a papain protease site which was subsequently found in all cytopathic BVD viruses examined with and without inserts (n = 10), though this additional protease site was not found in the same region in the ncpBVDV pairs or in low virulence ncpBVDV.