The objective of this study was to compare the pathogenicity of highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) infection between wild and domestic pigs based on clinical, immunological, and pathological evaluation. Upon challenge with HP-PRRSV, five wild pigs died compared to none of the domestic. Anti-PRRSV antibody titers were significantly (P < 0.05) higher in wild HP-PRRSV-infected pigs versus the domestic HP-PRRSV-infected pigs at 21 days post inoculation (dpi). Lung lesion scores at 7 dpi were also significantly (P < 0.01) higher in domestic infected pigs than wild infected pigs. The most striking difference was the viral tissue distribution between the wild and domestic HP-PRRSV-infected pigs. HP-PRRSV-positive cells were observed in bronchiolar, gastric, and renal tubular epithelial cells from wild HP-PRRSV-infected pigs only. The results in this study demonstrated a genetic difference exists between wild and domestic pigs, which could results in different clinical signs, immunological responses, and pathological outcomes to HP-PRRSV infection.