Porcine reproductive and respiratory syndrome virus (PRRSV) causes great economic losses to the swine industry worldwide. Typically， an N protein-coated indirect enzyme-linked immunosorbent assay (N-coated iELISA) is used to detect PRRSV antibodies. Non-structural protein (NSP) 4 is essential to the PRRSV life cycle and contains B-cell epitopes. Yet， no specific antibody against NSP4 has been detected in clinical samples. In this study， we developed an NSP4-coated iELISA and compared its effectiveness with the N-coated iELISA. The NSP4-coated iELISA was developed with a cut-off value of 0.406 at an optical density of 450 nm by testing a panel of 70 PRRSV positive and 80 PRRSV negative pig serum samples， which generated a specificity and sensitivity of 100%. Agreement between the NSP4-coated and N-coated iELISAs was 92.2%. Interestingly， 50 serum samples， mostly from pigs vaccinated with the HP-PRRSV live strain， tested positive for PRRSV antibodies with the NSP4-coated iELISA， but were negative with the N-coated iELISA. These results were further confirmed by western blot analysis and another iELISA based on the N-terminus of NSP2 (NSP2-1-coated iELISA). The agreement between the results of western blot analysis with the NSP4-coated and NSP2-1-coated iELISA analyses were 92% and 96.1%， respectively， showing that the developed NSP4-coated iELISA is a useful tool to discriminate a false negative from a true negative response to the HP-PRRSV vaccine.