cCoinfections involving porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) contribute to a group of disease syndromes known as porcine circovirus-associated disease (PCVAD). Presumably, PRRSV infection enhances PCV2 replication as a result of modulation of host immunity. The purpose of this study was to evaluate PCV2 replication and pathogenesis in pigs vaccinated with a PRRS modified live virus (MLV) vaccine and subsequently challenged with a combination of PRRSV and PCV2. During the early postchallenge period, the number of pigs with PRRSV-associated clinical signs was decreased, and average daily gain (ADG) was increased, in the vaccinated group, demonstrating the protective effect of PRRS vaccination. However, during the later postchallenge period, more pigs in the vaccinated group showed increased PCV2 viremia, decreased ADG, increased PCVAD clinical signs, and increased mortality. In this disease model, the early benefits of PRRSV vaccination were outweighed by the later amplification of PCVAD. P orcine circovirus type 2 (PCV2), a single-stranded DNA virus in the family Circoviridae, contributes to a group of syndromes collectively termed porcine circovirus-associated disease (PCVAD) (1). Two important clinical syndromes associated with PCVAD are PCV2-associated pneumonia and postweaning multisystemic wasting syndrome (PMWS) (1, 2). Management of PCV2 through the use of inactivated and subunit vaccines has led to the effective control of PCVAD in North America and Europe. However, the emergence of new PCV2 strains and the lack of PCV2 vaccination programs in other countries create an uncertain future for continued disease control.Porcine reproductive and respiratory syndrome virus (PRRSV) is a single-stranded RNA virus in the family Arteriviridae (3, 4). For the past 20 years, PRRSV has remained the most costly disease affecting swine production worldwide (5). PRRSV infection contributes to a number of immunological outcomes that increase the susceptibility of the host to secondary infections by primary and secondary pathogens (6-8). PRRSV is frequently isolated along with PCV2 (9) and is one of the major cofactors linked with increasing PCV2 replication and pathogenesis (10-12). Previous work by us and others has shown that a principal contribution of PRRSV is to increase PCV2 viremia (13). Increased PCV2 replication is likely the result of immune stimulation that results in more PCV2-permissive cells combined with PRRSV-induced immunomodulation. The complex etiology of PCVAD, including the role of PRRSV infection, has yet to be fully understood. In an extensive body of work, we identified the aberrant recognition of a nonneutralizing decoy epitope on the PCV2 capsid protein (CP) as a contributing factor in PCVAD immunopathogenesis. Natural PCV2 infection of a population produces a mixture of pigs that recognize the decoy and neutralizing epitopes, which may explain why only a subpopulation of infected pigs goes on to develop PCVAD (13-15).In this study, we to...