In 2004, a marked increase in the incidence and severity of porcine circovirus associated disease (PCVAD) was observed in eastern Canada. The severe outbreaks of PCVAD in Canada, followed by similar outbreaks in North Carolina and the Midwest United States raised concerns over introduction of a new and more virulent PCV2 variant into North America. Several research groups found the PCV2”b” cluster, previously not recognized in North America, to be associated with the majority of the recent severe PCVAD outbreaks. The first objective of this study was to compare the virulence of recent PCV2b isolates with well-characterized U.S. PCV2a isolates in the conventional specific pathogen free (SPF) pig model. The second objective of this study was to determine if infection with PCV2a isolates induces protective immunity against a recent PCV2b isolate. One-hundred and thirteen conventional SPF pigs were randomly assigned to treatment groups and rooms: pigs inoculated with PCV2a cluster isolates (ISU-40895 or ISU-4838), pigs inoculated with PCV2b cluster isolates (NC-16845 or Can-17639), and un-inoculated pigs. Necropsies were performed at 16 or 51 days post inoculation (p.i.). There were no significant differences in PCV2-associated lymphoid lesions between PCV2a and PCV2b clusters; however within the same cluster significant differences were found between isolates: ISU-4838 and Can-17639 inoculated pigs had significantly (P < 0.05) less severe lesions compared to ISU-40895 and NC-16845 inoculated pigs. To evaluate cross-protection, six pigs within each group were challenged on 35 days p.i. with an isolate from the heterologous cluster and were necropsied 51 days p.i. The severity of PCV2-associated lesions was reduced in pigs with prior exposure to an isolate from the heterologous cluster in comparison to singularly inoculated pigs. Results indicate that the virulence of PCV2a and PCV2b isolates is not different in the conventional SPF pig model; however, the virulence of isolates within the same cluster differs. Increased virulence as reported in the field associated with PCV2b isolates was not observed under the conditions of this study. Moreover, cross-protection between PCV2a and PCV2b exists. In summary, convincing evidence that the recently identified PCV2b isolates are more virulent than PCV2a isolates that have been circulating in the pig population is lacking and thus the introduction of a new more virulent strain of PCV2 does not fully explain the re-emergence of severe PCVAD in North America in 2004. Another possible explanation for the recent devastating PCVAD outbreaks in North American could be the presence of more virulent known (i.e. PRRSV) or unknown concurrent infection that specifically enhances replication of PCV2 and thereby increases disease severity.