Background: Porcine circovirus type 2 (PCV2) remains one of the most important pathogens that infects swine, causing considerable economic losses worldwide. PCV2 vaccines are commercially available, and the development of experimental vaccines that could confer better protection against emerging genotypes is underway. The expression of virus-like particles (VLPs) carrying different PCV2 capsid (Cap) peptides in E. coli was recently reported. These chimeric particles were adjuvated with an oil-in-water emulsion with polymer and induced different titers of serum IgG in BALB/c mice after a single subcutaneous injection. The aim of this study was to assess the immune response and protective efficacy elicited by VLPs carrying the PCV2b Cap carboxy-terminal peptide in the target species. Methods: Domestic pigs (Sus scrofa domesticus) were immunized intramuscularly with 25 μg of adjuvated chimeric VLPs on days 0 and 14 and challenged on day 28 with a PCV2b Mexican isolate. PCV2 peptide-specific IgG seroconversion, serum cytokines, viral load in nasal swabs and organs, and histopathological score were determined. Results: IgG levels peaked 28 days post-immunization. Interleukin-12 and -18 and interferon-gamma increased 21 days after immunization. In addition, genomic material of PCV2 was detected in nasal swabs from one specimen on day 7, two specimens on day 14, and two specimens on day 21 following viral challenge. Finally, histological lesions were not less severe in immunized specimens compared to non-vaccinated/challenged specimens. Conclusions: These results suggest that immunization with chimeric VLPs could contribute to controlling viral shedding in pig herds where a PCV2b genotype is most prevalent.