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Bovine viral diarrhea virus (BVDV) is an economically important pathogen that is endemic in cattle populations of many countries. This virus can also infect pigs, camelids, and a wide range of ruminants including sheep, goats, and wild ruminants. BVDV infections are often subclinical, but can also be associated with severe reproductive losses and signs of respiratory or gastrointestinal disease. BVDV isolates circulating in animal populations are genetically and antigenically highly diverse. Two species of BVDV are currently recognized within the genus Pestivirus, BVDV-1 and BVDV-2. Furthermore, at least 21 BVDV-1 subgenotypes (1a-1u) and four BVDV-2 subgenotypes (2a-2d) have been described to date. The accumulation of mutations during viral replication due to the minimal proofreading activity of the BVDV RNA polymerase is believed to be the main driving force for the generation of altered genomic sequences. Previous studies have demonstrated that great numbers of nucleotide and amino substitutions occurred during acute BVDV infections in pregnant cattle. As this virus does not possess strict host specificity, cross-species infections provide a further opportunity for viral diversification. However, only limited information exists regarding genomic changes arising during BVDV infections in species other than cattle. The purpose of this research was thus to determine the changes introduced in the open reading frame (ORF) of the BVDV genome during serial infection of pregnant cattle, sheep, and swine. Serial experimental inoculations were performed in six pregnant heifers, six pregnant ewes, and six pregnant gilts using the BVDV-1b isolate AU526 in the first dam of each species and serum from the preceding acutely infected dam thereafter. The complete ORF sequences of AU526 and 36 isolates from acutely infected pregnant dams and their congenitally infected offspring were then determined. These sequences were compared to determine the timing, number, location, and type of substitutions introduced during serial infection of pregnant cattle, sheep, and swine. Greater numbers of nucleotide and amino acid substitutions occurred during serial infection of pregnant sheep and swine than of pregnant cattle. Furthermore, multiple identical amino acid changes were detected in viral isolates obtained from animals of the same species. These changes were more abundant and more rapidly introduced in sheep and swine, and occurred primarily in the E2 and Erns coding regions of the viral genome. Furthermore, most substitutions involved the same amino acid residues in sheep and swine. In contrast, changes repeatedly identified during serial infection of pregnant cattle were not observed in isolates from pregnant sheep and swine serially infected with AU526. Altogether these results suggest that BVDV infections in species other than cattle may serve as a significant source of viral genetic diversity and may be associated with adaptive changes.