Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases (PCVAD) in swine. Coinfections of PCV2 with other swine pathogens increase the severity of PCVAD. Induction of proinflammatory cytokines by coinfecting pathogens may attribute to the exacerbation of PCVAD during coinfections. An interferon-stimulated response element (ISRE) sequence was identified in the origin of replication of PCV2 genome. To assess the role of ISRE in PCV2 pathogenesis during coinfection, an ISRE-mutant PCV2 was constructed and used to experimentally infect pigs with either ISRE mutant or wildtype PCV2 singly or in combination with porcine reproductive and respiratory syndrome virus (PRRSV). The results showed that, during early stage of infection at 14 days post-inoculation (dpi), the ISRE mutation reduced viral replication and elicited low antibody responses. However, at 28 dpi viremia in pigs infected with the ISRE-mutant was on an upward trend, and microscopic lesion scores in pigs inoculated with the ISRE-mutant were significantly more severe than in wildtype PCV2-infected pigs. Coinfection with PRRSV caused an opposite shift in the in vivo dynamics of the ISRE-mutant at 14 dpi with the lymph node histopathological lesions being significantly more severe in pigs coinfected with the ISRE-mutant PCV2 and PRRSV than in pigs coinfected with wildtype PCV2 and PRRSV. PCV2 genomic copy numbers in pigs coinfected with ISRE-mutant and PRRSV were also higher than those coinfected with wildtype PCV2 and PRRSV. The results suggested that the ISRE element in PCV2 genome may play a potential role in viral pathogenesis.