The major histocompatibility complex (MHC) of cattle is known as BoLA and located on chromosome 23. It was found that BoLA shows significant differences in genome organization with human MHC but shares similar protein structures and functions. Among the entire BoLA class II subregion, BoLA-DRB3 is the most polymorphic and functional gene that has been intensively studied its correlation with various cattle infection diseases and economic traits. In particularly, BoLA-DRB3 polymorphism has been linked to resistance or susceptibility of bovine leukemia virus (BLV) infection outcome, transmission and disease progression. BLV leads to enzootic bovine leucosis which is the most common neoplastic disease in cattle and leads to severe financial loss in industry worldwide. As a result, genetic selection of BLV-resistant animals, as well as the preferential culling of BLV-susceptible animals, based on BolA-DRB3 polymorphism, serves as a promising strategy for the control of BLV spreading and disease risk estimation, especially in the time there are no vaccines and treatment available. In this review, we outline the BoLA system in protein and genetic levels and focus particularly on the literatures of association between BoLA-DRB3 polymorphism with BLV.