Porcine circovirus type 2 (PCV2) is associated with several disease manifestations in pigs including postweaning multisystemic wasting syndrome (PMWS). The hallmark microscopic lesions of PCV2-infection are lymphoid depletion or granulomatous lymphadentitis (or both) and the presence of PCV2 antigen or nucleic acids associated with the lymphoid lesions. PCV2 alone is limited in its ability to induce the full spectrum of disease and lesions associated with PMWS in pigs;PCV2 is widespread in the global swine population and in order to establish a PCV2 model in conventional pigs it was necessary to identify a method to derive pigs free of PCV2 or anti-PCV2 antibodies. We obtained more than 500 PCV2-free pigs from six seropositive breeding herds and demonstrated that segregated early weaning is an effective technique to derive PCV2-free pigs from positive breeding herds for research or for commercial production;We determined that vaccination with commercially available adjuvanted bacterins enhances PCV2 replication and PCV2-associated lesions. We also found that timing of vaccination in relationship to PCV2 infection is important in the outcome of vaccine-induced enhancement of PCV2 replication and PCV2-associated lesions;Field reports indicated that PCV2-infection may also decrease the efficacy of vaccines used at the time of PCV2 infection. When we vaccinated pigs with a modified-live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine 14 days post PCV2 inoculation we found that PCV2 infection significantly decreased the efficacy of the PRRSV vaccine as measured by gross and microscopic lesions;It is thought that coinfections may be an important trigger for progression of PCV2 to PMWS and other PCV2-associated diseases. We experimentally confirmed that PCV2 and porcine parvovirus coinfection resulted in clinical PMWS in conventional pigs whereas singular infection does not. Coinfecting conventional pigs with PCV2 and Mycoplasma hyopneumoniae resulted in severe respiratory disease, reduced average daily gain, and severe lung and lymphoid lesions associated with PCV2-antigen in dual-infected pigs implying that M. hyopneumoniae potentiates the severity of PCV2-associated lung and lymphoid lesions and increases the incidence of PMWS;Host and virus differences may also be important in the outcome of PCV2 infection. In our conventional pig model, we found a predisposition of Landrace pigs to PCV2-associated lesions and disease when compared to Duroc and Large White pigs. Finally, we were the first to experimentally confirm that PCV2-field isolates differ significantly in virulence in our conventional pig model.