The proposal was submitted in response to a request for proposals to investigate PCV2 associated disease. The three objectives were (1) analyze PCV2 genetic sequences from herds experiencing an outbreak of severe PMWS in late 2005, (2) identify novel co-factors associated with severe disease, (3) determine if the PCV2 isolates from the Kansas Cluster cause severe PMWS. A fourth objective was added later to look at the effectiveness of commercial vaccines. The approach focused on affected pigs from herds experiencing PMWS and PDNS in Kansas. DNA sequencing was used to characterize the PCV2 viruses involved in the outbreak. PCR and virus isolation were used to identify other viruses, which might function as co-factors. Tissue homogenates from affected pigs were used to reproduce the disease. And finally, a random blind study was incorporated to evaluate the effectiveness of PCV2 vaccines. The results from this study demonstrate that (1) The recent outbreak of PCVAD is associated with the emergence of the PCV2b genotype. Severe PCVAD in a group of Kansas herds was a disease problem not previously encountered in this region. Interestingly, the clinical disease pattern was present in herds negative for PRRSV, a cofactor frequently linked to PCVAD. The PCV2b genotype was tracked to approximately 70 PCVAD affected herds. The original source of the virus was never identified. (2) Several differential diagnostic assays were developed that can distinguish PCV2a from PCV2b. We incorporated sequence differences between PCV2a and PCV2b to develop genotype specific assays. These assays are being used by the Kansas State Veterinary Diagnostic Laboratory to track infections of PCV2a and b in the field. The assays are available for use by other diagnostic laboratories. (3) A variety cofactors are implicated in the etiology of disease. Over the course of the study we identified a “zoo” of bacteria and viruses in PCVAD pigs. The importance of cofactors in the control of the disease remains unknown. It appears that the effectiveness of PCV2 vaccines means that cofactors, for the present time, are not as important. (4) Vaccines are effective in controlling the disease. The results from field studies demonstrated that vaccination reduces mortality, morbidity and virus load; while increasing PCV2 antibody levels and significantly improving weight gain. These studies place a clear economic benefit to vaccination. Vaccines are also helpful in re-defining the disease.