Soybean mosaic virus (SMV) causes one of the most destructive viral diseases in soybean (Glycine max). The soybean cultivar Dabaima carries the Rsc4 gene for SMV resistance. The genomic region containing Rsc4 was previously localised within a 100-kb region on chromosome 14. The corresponding region contains three complete nucleotide-binding site (NB) and leucine-rich repeat (LRR) type genes and one incomplete gene that is likely non-functional. Quantitative real-time polymerase chain reaction analysis revealed that three candidate genes encoding NB-LRR proteins were differentially expressed in resistant and susceptible lines when the plants were inoculated with SMV strain SC4. To test the involvement of the three candidate genes in Rsc4 mediated resistance, the three genes were silenced using a Bean pod mottle virus (BPMV)-based vector construct. Silencing of three candidate genes attenuated the Rsc4-mediated resistance and induced SMV symptoms in Dabaima plants. Moreover, Rsc4 candidate genes were 78% downregulated when compared with the empty BPMV vector-treated plants. From these results, we concluded that at least one of the three candidate genes encoding NB-LRR proteins is required for Rsc4 resistance to SMV.