The macrophage scavenger receptor CD163 is a major determinant for the entry of porcine reproductive and respiratory syndrome virus (PRRSV). The present study was undertaken to assess the functional significance of the intracellular region of CD163 for PRRSV infection. We stably transfected non-susceptible BHK cells with plasmids encoding full-length and cytoplasmic-domain-deleted (tailless) CD163 and evaluated their permissiveness to PRRSV. The experimental data revealed that the tailless CD163 was not only completely sufficient for converting non-target cells to PRRSV susceptibility, but it also notably enhanced virus replication, with significant increases in viral protein synthesis and progeny release. Taken together, our results suggest that the intracellular domain of CD163 may be associated with an important yet-unknown function during PRRSV infection.