The aim of this study was to analyze the immunogenic response elicited in swine by two synthetic peptides derived from GP5 to understand the role of lineal B epitopes in the humoral and B-cell-mediated response against the porcine reproductive and respiratory syndrome virus (PRRSV). For inoculation, twenty-one-day-old pigs were allocated into six groups: control, vehicle, vaccinated (Ingelvac-PRRSV, MLV (R)), non-vaccinated and naturally infected, GP5-B and GP5-B3. At 2 days post-immunization (dpi), the GP5-B3 peptide increased the serum concentrations of cytokines associated with activate adaptive cellular immunity, IL-1 beta (1.15 +/- 1.15 to 10.17 +/- 0.94 pg/mL) and IL-12 (323.8 +/- 23.3 to 778.5 +/- 58.11 pg/mL), compared to the control group. The concentration of IgGs anti-GP5-B increased in both cases at 21 and 42 dpi compared to that at 0 days (128.3 +/- 8.34 ng/mL to 231.9 +/- 17.82 and 331 +/- 14.86 ng/mL), while IgGs anti-GP5-B3 increased at 21 dpi (105.1 +/- 19.06 to 178 +/- 15.09 ng/mL) and remained at the same level until 42 dpi. Also, antibody-forming/Plasma B cells (CD2+/CD21-) increased in both cases (9.85 +/- 0.7% to 13.67 +/- 0.44 for GP5-B and 15.72 +/- 1.27% for GP5-B3). Furthermore, primed B cells (CD2-/CD21+) from immunized pigs showed an increase in both cases (9.62 +/- 1.5% to 24.51 +/- 1.3 for GP5-B and 34 +/- 2.39% for GP5-B3) at 42 dpi. Conversely the na & iuml;ve B cells from immunized pigs decreased compared with the control group (8.84 +/- 0.63% to 6.25 +/- 0.66 for GP5-B and 5.78 +/- 0.48% for GP5-B3). Importantly, both GP5-B and GP5-B3 peptides exhibited immunoreactivity against serum antibodies from the vaccinated group, as well as the non-vaccinated and naturally infected group. In conclusion, GP5-B and GP5-B3 peptides elicited immunogenicity mediated by antigen-specific IgGs and B cell activation.