A noncytopathic bovine viral diarrhea virus (BVDV), BVDV-890, isolated from a yearling heifer that died with extensive internal hemorrhages, was compared for virulence in calves with noncytopathic BVDV-TGAN, isolated from an apparently healthy persistently infected calf. After challenge exposure with BVDV-890, nonimmune calves (n = 7) developed fever > 40 C, diarrhea, leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Most calves (n = 6) died or were euthanatized by 19 days after challenge exposure. Challenge exposure with BVDV-890 did not induce disease in 2 calves that had congenital persistent infection with BVDV or in 3 calves that had neutralizing antibody titer > 4 against BVDV-890. After challenge exposure with BVDV-TGAN, nonimmune calves (n = 7) developed fever > 40 C and, rarely, diarrhea or lymphopenia. All of those calves survived challenge exposure. The average maximal titer of BVDV-890 isolated from serum was 1,000 times that of BVDV-TGAN. In calves infected with BVDV-890, the average maximal percentages of lymphocytes and platelets associated with virus were greater than those found in calves infected with BVDV-TGAN. Additional findings of epidemiologic significance were prolonged shedding of virus and delayed production of viral-neutralizing antibody in 1 calf challenge-exposed with BVDV-890. Also, after production of neutralizing antibody, mutant virus that was refractory to neutralization was isolated from calves challenge-exposed with BVDV-TGAN.