Porcine circovirus type 2 (PCV2) is an important pathogen of swine and is associated with postweaning multisystemic wasting syndrome which is characterized by follicular and interfollicular lymphoid depletion and a concurrent macrophage infiltration of lymphoid tissues. The mechanism of the lymphocyte depletion in PCV2 infected pigs and the specific immune cell populations in which PCV2 replicates remains unknown. The objectives of these studies were to evaluate PCV2 replication in specific immune cell populations in vitro and in vivo, and investigate the effects of PCV2 infection and replication on activated immune cells in vitro. We demonstrated that mitogen stimulation/activation increases virus replication in peripheral blood mononuclear cells (PBMCs) in vitro and the virus replication level was higher with pokeweed mitogen (PWM) stimulation compared to concanavalin A (ConA) stimulation. PCV2 replicates in T and B lymphocytes, which appear to be the primary cells that support virus replication while monocytes appear to be a site for PCV2 persistence in the infected host. We found that PCV2 replicates in most tissues except thymus and lymphoid tissues near the site of infection play an important role in PCV2 replication and persistence. Our investigation of the effect of PCV2 infection and replication on activated porcine PBMCs in vitro demonstrated that PCV2 infection does not impair the ability of PBMCs to proliferate in response to ConA/PWM stimulation. Increased apoptosis was associated with PCV2 infection in the presence of PWM, but not ConA, indicating that PCV2 induced apoptosis requires a specific stimulation/trigger. In the presence of PCV2 alone, apoptosis was decreased suggesting that PCV2 may persist in immune cells by inhibiting apoptosis. The relationship between virus replication and cellular proliferation was investigated and no significant differences were observed between the levels of PCV2 replication product, spliced capsid mRNA, in PBMCs stimulated at various times prior to PCV2 infection or between proliferating and non-proliferating PBMCs with ConA/PWM stimulation. These findings suggest that PCV2 replication requires a specific stimulation/trigger and is not dependent just on cell division/proliferation. These studies provide important information on understanding the pathogenesis of PCV2-induced diseases.