The minor glycoproteins (GPs) of PRRSV, GP2, GP3, and GP4, form a heterotrimer that is required for viral infectivity, presumably due to its interaction with the key cellular receptor CD163. These 3 GPs are encoded by open reading frames (ORFs) 2a, 3 and 4 (herein referred to as ORFs 2–4), respectively. The goal of this study was to investigate the immunogenicity of the PRRSV-2 minor GPs. Through the use of reverse genetics, a chimeric virus (designated SDFL24) was constructed by replacing ORFs 2–4 of the PRRSV-1 strain SD01-08 with the corresponding genes of the PRRSV-2 strain FL12. While the parental PRRSV strain SD01-08 was not neutralized by convalescent antisera raised against FL12, the chimeric virus SDFL24 gained susceptibility to neutralization by FL12-specific antisera, indicating that viral proteins encoded by ORFs 2–4 are targets of antibody neutralization. When inoculated into pigs, the chimeric virus SDFL24 elicited T-cell responses against peptides derived from FL12 minor GPs, whereas the parental virus SD01-08 did not. After challenge infection with FL12, pigs previously infected with SDFL24 developed robust kinetics of FL12-specific neutralizing antibodies as compared to those previously infected with the parental strain SD01-08. Finally, the pigs recovered from SDFL24 infection were better protected from a subsequent challenge infection with FL12 than those previously infected with SD01-08. Collectively, the results indicate that PRRSV-2 ORFs 2–4 are capable of inducing protective immunity.