A recombinant replication-defective adenovirus expressingthe major epitopes of porcine circovirus-2 (PCV-2) capsidprotein (rAd/Cap/518) was previously constructed and shownto induce mucosal immunity in mice following intranasaldelivery. In the present study, immune responses induced byintranasal immunization with a combination of rAd/Cap/518and cytosine-phosphate-guanosine oligodeoxynucleotides(CpG ODN) were evaluated in mice. The levels ofPCV-2-specific IgG in serum and IgA in saliva, lung, andintestinal fluids were significantly higher in the groupimmunized with rAd/Cap/518 and CpG ODN than animalsimmunized with rAd/Cap/518 alone. The frequencies ofIL-2-secreting CD4+ T cells and IFN-γ-producing CD8+ T cellswere significantly higher in the combined immunizationgroup than mice immunized with rAd/Cap/518 alone. Thefrequencies of CD3+, CD3+CD4+CD8−, and CD3+CD4−CD8+T cells in the combined immunization group were similar tothat treated with CpG ODN alone, but significantly higherthan mice that did not receive CpG ODN. PCV-2 load afterchallenge in the combined immunization group wassignificantly lower than that in the phosphate-buffered salineplacebo group and approximately 7-fold lower in the grouptreated with CpG ODN alone. These results indicate thatrAd/Cap/518 combined with CpG ODN can enhance systemicand local mucosal immunity in mice, and represent apromising synergetic mucosal vaccine against PCV-2.