Porcine circovirus (PCV) is a member of the genus Circovirus of the Circoviridae family. This family consists of a diverse group of animal viruses that possess a small, closed circular, single-stranded DNA genome that replicates through double-stranded intermediates. Two genotypes of PCV have been identified. PCV type 1 (PCV1) is non-pathogenic, while PCV type 2 (PCV2) has been implicated as the etiological agent of a collection of disease syndromes labeled porcine circovirus associated disease (PCVAD) which include postweaning multisystemic wasting syndrome (PMWS) in swine.;In late 2005, a postweaning, high mortality syndrome spread rapidly through fattening barns in swine dense areas of the United States. Diagnostic investigations consistently isolated porcine circovirus type 2 (PCV2) from diseased tissues. Subsequent genetic analysis revealed the infectious agent was PCV2b. Prior to late 2004, only PCV2a, but not PCV2b, had been reported in North America. In the first manuscript in this thesis, we demonstrate an acute high mortality disease in germ-free pigs using infectious viruses generated from DNA clones constructed from PCV2a and PCV2b isolates identified in the 2005 outbreak. Clinical signs exhibited by diseased pigs included anorexia, dyspnea and listlessness. Mortality was typically observed within 12 hours of onset of dyspnea. The most striking microscopic lesions in affected animals were severe hepatic necrosis and depletion of germinal centers in lymph nodes with associated abundant PCV2 viral antigen. Clinical signs and lesions observed in this study were comparable to those reported in experiments with germ-free pigs inoculated with a PCV2a isolate while concurrently receiving immune-stimulation or co-infection with porcine parvovirus. The animals in this study were confirmed to be free of detectable porcine parvovirus, bovine viral diarrhea virus, porcine reproductive and respiratory syndrome virus, porcine hepatitis E virus, and aerobic and anaerobic bacteria. Thus, in these studies, both PCV2a and PCV2b isolates were singularly capable of inducing high mortality in the absence of any recognized infectious co-factor in the gnotobiotic model.;Porcine circovirus associated disease is a disease complex affecting swine around the world. Although PCV2 is believed to negatively affect the host's immune system, the mechanism by which PCV2 induces disease is not completely understood. The second manuscript in this thesis describes a series of PCV2 experiments using the gnotobiotic pig model in which a correlation was noted between abnormal leukograms and clinical disease in PCV2-infected pigs. The leukogram was characterized by a lymphopenia beginning within 14 days post inoculation (dpi) followed by an absolute neutrophilia approximately one week later. No significant changes in the circulating monocyte, basophil, and eosinophil cell populations were detected. The combination of an absolute neutrophilia and lymphopenia produced a neutrophil/lymphocyte ratio that was predictive of clinical disease and was inversely correlated with the presence of neutralizing antibodies.