Infection with classical swine fever virus (CSFV) is costly to the livestock industry. Several genomic sequences including velogenic strains and low virulent strains have been identified. However, the reasons for the virulence of the virus have remained unclear. Based on selective pattern and pressure strength, we classified all genes of CSFV into three classes. Among these genes, the E2 gene was under the strongest positive selection. Based on the analysis of 85 representative E2 gene sequences, the location and intensity of positive selection in CSFV isolates from group one and group two were identified. These results suggest that these two groups employ evolutionary difference. Moreover, the mutations, potentially driven by positive selection, can be correlated with the virulence of CSFV by altering the conformation and function of E2 and/or changing its glycosylation pattern. Based on these results, a model for the evolution of virulence of CSFV is proposed. The results provide a link between epidemiology and the gene function of CSFV, and may shed light on the molecular mechanism underlying the variation of CSFV virulence.