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Porcine reproductive and respiratory syndrome virus (PRRSV), the causative agent of porcine reproductive and respiratory syndrome, is responsible for serious disease in pigs resulting in substantial economic losses in the porcine industry. An attenuated vaccinestrain, HuN4-F112, was obtained by passaging virulent PRRSV strain HuN4 on Marc-145cells (for 112 passages), and the full-genomic sequence was determined. To understandthe molecular basis of attenuation of PRRSV, we compared and analyzed the genomic sequences of HuN4/HuN4-F112, together with those of other four virulent parental/attenuated vaccine strains. Among the 19 PRRSV proteins, two (NSP6 and NSPB) werehighly conserved, without any mutations and considered irrelative to attenuation. The mutation rates of envelope-associated structural proteins were obviously higher than those of most non-structural proteins. It is interesting that the gene of the smallests tructural protein, E protein, had the highest mutation rate among all of the structural genes analyzed, and also harbored a highly variable region. Our results indicate that determinants of PRRSV attenuation are multigenic products of both non-structural and structural genes. To our knowledge, this is the first report showing that the envelope-associated structural proteins (including E and GP2-GP5 proteins) may play a significant role. These findings contribute towards our understanding of PRRSV attenuation and will provide an important clue for further study.