Host genetic differences in viral load (VL) and weight gain (WG) during porcine reproductive and respiratory syndrome virus (PRRSV) challenge were assessed for thirteen trials of ~200 commercial crossbred piglets each, from several different commercial suppliers. Piglets were experimentally infected with PRRSV isolates NVSL-97-7895 (NVSL) or KS-2006-72109 (KS06). VL and WG were moderately heritable and were antagonistically related for both virus isolates. The genetic correlation of host response to NVSL with host response to KS06 was high for both VL and WG. Consistent with previous findings, animals that were heterozygous (AB) for the WUR10000125 (WUR) marker on Chromosome 4 (SSC4) had significantly lower VL than their AA counterparts when infected with either virus isolate; however, a significant increase in WG was only observed when piglets were infected with the NVSL isolate. These results suggest that selecting for increased resistance or reduced susceptibility to PRRSV may be effective across virus isolates. Selecting for the AB genotype for WUR is expected to reduce VL across PRRSV isolates but its effect on WG during infection may differ between virus isolates.