It seems well established that CpG oligonucleotide Th1-biased adjuvant activity can be improved when closely associated with a variety of antigens in, for example, microparticles. In this context, we prepared 1-micron near non-charged poly(lactic-co-glycolic) acid (PLGA) 502 and PLGA 756 microparticles that loaded with high-efficiency antigen (50% ovalbumin (OVA), approximately) into their matrix and CpG-chitosan complexes (near to 20%) onto their surface maintaining OVA and CpG integrity intact. In the intradermal immunization studies, whereas OVA microencapsulated into PLGA 756 alone induced a strong humoral immune response assisted by a very clear Th1 bias (IgG2a/IgG1=0.88) that was decreased by CpG co-delivery (IgG2a/IgG1=0.55), the co-encapsulation of CpG with OVA in PLGA 502 particles significantly improved the antibody response and isotype shifting (IgG2a/IgG1=0.73) in comparison with mice immunized with OVA-loaded PLGA 502 (IgG2a/IgG1=0). This improvement was not correlated with the cellular immune response where the effect of co-encapsulated CpG was rather negative (2030 and 335 pg/mL IFN-gamma for OVA PLGA 502 and OVA CpG PLGA 502, respectively). These results underscore the critical role of polymer nature and microparticle characteristics to show the benefits of co-encapsulating CpG motifs in close proximity with an antigen.