CD163 and sialoadhesin had been reported as the two receptors for porcine reproductive and respiratory syndrome virus (PRRSV) infection. The signaling pathway activated by PRRSV entry was seldom reported. In our studies, we demonstrated that PRRSV entry triggers FAK, PI3K, AKT and Rac1 activation. The signaling pathway FAK-PI3K-AKT-Rac1 is essential for PRRSV entry. Blocking FAR by PF573228 attenuates the activation of PI3K, ART, Rac1 and the cytoskeleton remodeling induced by virus entry. Inhibitors to FAR, PI3K, AKT and Rac1 can significantly inhibit the virus entry. In conclusion, our observations reveal that PRRSV triggers the activation of FAK-PI3K-AKT-Rac1 signaling pathway to facilitate its entry into cells. (C) 2015 Elsevier Inc. All rights reserved.