Porcine circovirus type 2 (PCV2) is a swine pathogen that causes postweaning multisystemic wasting syndrome, associated with a number of other disease symptoms in pigs. It has caused high economic losses for pig industries in China and worldwide. Vimentin is a cytoskeletal protein involved in the lifecycle of numerous viruses. In this study, the role of Vimentin in PCV2 replication in pig alveolar macrophage (3D4/21) cells was studied. A 3D4/21 cell line overexpressing Vimentin was established using a lentivirus expression system, in which PCV2 replication was significantly enhanced. Meanwhile, in the Vimentin silenced 3D4/21 cells, PCV2 replication was significantly reduced. Furthermore, we found that PCV2 infection in 3D4/21 cells promoted Vimentin phosphorylation and rearranged Vimentin distribution in cells. By inhibition of CaMKII pathway, Vimentin phosphorylation was significantly suppressed and PCV2 replication was significantly inhibited. The results in this study indicated that in 3D4/21 cells, PCV2 promoted CaMKIIγ-medicated Vimentin phosphorylation and altered its cellular distributions to accomplish its own replication.