Most monoclonal antibodies (mAbs) to porcine reproductive and respiratory syndrome virus (PRRSV) are specific for its nucleocapsid (N) protein and non-neutralizing. A few mAbs generated to the primary envelope glycoprotein GP5, the matrix (M) protein and a minor envelope glycoprotein GP4 possess low virus neutralizing activity but anti-GP5 mAbs possess the highest neutralizing activity. The neutralizing activity of serum from PRRSV-infected pigs also correlates with anti-GP5 Ab titers. The primary neutralization epitope is located in the most hydrophilic GP5 segment in the middle of the ectodomain. For the North American PRRSV prototype the epitope is ³⁷SHLQLIYNL. Critical residues are H³⁸, Q⁴⁰, I⁴², Y⁴³. N⁴⁴. H³⁸ is replaced by T in the epitopes of the European PRRSV prototype explaining some differences in specificity. The neutralization epitopes are highly conserved among field isolates and during long-term pig infection or repeated passages in pigs inspite of the accumulation of many amino acid changes in the two hypervariable segments flanking the GP5 neutralization epitope. This suggests that neutralization escape plays no role in PRRSV evolution and that the center portion of the GP5 ectodomain is highly conserved because it has some critical function in virus replication. Indirect peptide ELISA has shown that Ab responses to both the GP5 neutralizing epitope and the N-protein vary greatly and independently between individual pigs. Some pigs generate neutralizing Abs rapidly, whereas other pigs fail to generate significant neutralizing Abs until 6-12 weeks post infection (p.i.). In contrast, viremia consistently peaks at 7-14 days p.i. and then declines rapidly in a manner unrelated to the formation of neutralizing Abs. These results suggest that the decline in viremia may be due to exhaustion of permissive macrophages rather than Ab neutralization. This could also explain the partial resistance of pigs to early infection in the absence of neutralizing Abs. The role of the 2-4 N-glycans that are associated with the neutralization epitope in modulating its expression and/or in virus infection/replication is uncertain. Infection of pigs with a natural mutant that lacks the two N-glycans upstream of the neutralization epitope of PRRSV strain VR2332 induced a ten-fold higher neutralizing Ab response than the latter and the Abs neutralized the mutant strain 10-fold more efficiently. In contrast, the neutralizing Ab response to a natural mutant lacking the N⁴⁴-glycan was greatly reduced compared to that induced by VR2332. Peptide ELISA results revealed the presence of anti-GP5 and anti-N-protein Abs in pigs of herds that were considered free of PRRSV infection. These results raise the possibility of more wide spread PRRSV infections by strains that cause only asymptomatic infections.