A high rate of genetic and antigenic variability is known to exist among PRRS viruses and has garnered great attention from the swine industry since such a phenotypic variation is perceived to interfere with effective immune protection particularly from “heterologous” strains. Therefore, molecular technology, such as sequencing or RFLP, is frequently used to predict the relatedness of PRRS viruses circulating within and between herds. However, genetic relatedness has not always been well correlated with immunological relatedness. As neutralizing antibody has been reported to play a role in protection from re-infection by the homologous virus, our study was intended to evaluate the correlation between genetic variation, in vitro virus neutralization and in vivo cross protection among PRRS viruses. The study revealed that the serum-virus neutralization test could be a good tool to predict the level of cross protection among PRRS viruses. The study also demonstrated that the effectiveness of virus neutralization may be attributed to change in certain epitopes but not to total sequence homology, which should be taken into consideration when interpreting sequence data. Those specific changes could be used as surrogate markers for the degree of cross neutralization among PRRS viruses by neutralizing antibody without doing animal trials every time, although it remain to be further studied whether or not sites identified can be used as surrogate genetic markers for cross protective immunity against various PRRS viruses.