PCV2 (porcine circovirus type 2) co-infection with porcine reproductive and respiratory virus (PRRSV) may increase porcine circovirus associated disease (PCVAD) severity and cause economic damage. Vaccination or not is controversial to control PCVAD, especially in PRRS. PRRSFREE® composed of PRRSV antigen fused with an antigen delivery platform including detoxified PE (Pseudomonas exotoxin) and ER retention signal can prevent PRRSV infection in Taiwan, Russia and Philippines. Using the same strategy, PCV2 subunit vaccine composed of modified- PCV2 ORF2 fused with the antigen delivery platform could induce stronger interferon-gamma (IFN-Ƴ) production in peripheral blood mononuclear cells (PBMC), reduce the viral load and increase the survival rate after PCV2 challenging. Moreover, combination of PRRSFREE® and PCV2 subunit vaccine could trigger immune response against both PRRSV and PCV2 at the same time. PBMC of the vaccinated pig could produce more IFN-Ƴ after treated with PRRSV or PCV2. According to the challenging assay, combination of PRRSFREE® and PCV2 subunit vaccine could increase the average daily weight gain; reduce both PRRSV and PCV2 viral load and increase the survival rate. This study demonstrates that the vaccine used in this study is very safe, can reduce PCV2 /PRRSV viremia and the symptoms after the infection.Vaccination with the novel combo subunits is potential to control PCVAD diseases.