ABSTRACT Objective: This study investigates the long-term evolutionary dynamics of porcine reproductive and respiratory syndrome virus (PRRSV-1) in an endemically infected and vaccinated pig herd. Methods: Over a one year and a half period, piglets from seven farrowing batches in a 300-sow PRRSV-vaccinated farm were monitored from birth to nine weeks of age by RT-qPCR. Eighty-five PRRSV-positive samples were subjected to whole genome sequencing (Illumina Miseq), and 251 samples to ORF5 sequencing. Farm-specific PRRSV variants’ impact on anti-PRRSV antibodies was evaluated using ELISA and neutralizing antibody assays. The replication kinetics and cytokine inhibition capabilities (IFN-α and TNF-α) of these variants were assessed in porcine alveolar macrophages. Results: The study revealed fluctuating PRRSV-1 incidences in farrowing units and nurseries, attributed to two key evolutionary events: an escape variant emergence and a lateral introduction of a new strain. Initially, strain 1 variant α was swiftly replaced within weeks by variant 1β (99.5% genomic similarity), with twenty-five amino acid mutations, primarily in nsp1α, GP2, GP3, and GP5, including an additional glycosylation site and a deletion downstream the neutralization epitope of GP5. This shift to 1β correlated with increased incidence in nurseries and higher viral loads, with sera from 1α-exposed animals showing reduced neutralization against 1β. Consistently for in vitro assays, variant 1β demonstrated enhanced replication in porcine alveolar macrophages but no difference regarding IFN-α or TNF-α responses. Later, a new strain (strain 2, 83.3% similarity to strain 1) emerged and led to incidence resurgence because of the low cross reactivity with the previous antibodies. Conclusion: The study highlights PRRSV’s rapid adaptability and challenges in controlling its spread, underscoring the necessity for more effective vaccines and eradication approaches.