Elite populations of farm animals under genetic selection are often maintained in high hygiene conditions, yet the commercial populations may be raised in, and are expected to perform well in, environments of varied hygiene levels. This presents special challenges to genetically improve those traits for which genotype by environment interactions are important. Twelve immune-related genes were studied for associations with general mortality and other performance traits in 3 elite commercial broiler chicken lines raised in high and low hygiene environments. The genes were toll-like receptor 4, MD-2 (accessory protein of TLR4), interferon-γ, transforming growth factor-β 3, inducible nitric oxide synthase, macrophage migration inhibitory factor, interleukin-2, caspase-1, inhibitor of apoptosis protein-1, tumor necrosis factor-related apoptosis-inducing ligand, chicken B-cell marker, and bone morphogenetic protein-7. From a total of 56 identified single-nucleotide polymorphisms (SNP) in 12 genes, 14 SNP that had moderate allelic frequencies in at least 2 of the 3 lines were typed in about 100 progeny-tested sires from each of 3 elite commercial broiler chicken lines using restriction fragment length polymorphism techniques and then used in association analysis. The traits measured on the progeny (total progeny = 145,467) were: mortality from hatching to 14 d and from 14 to 40 d of age, BW at 7 and 40 d of age, feed conversion, ultrasound breast depth, percentage of breast, eviscerated carcass weight, twisted legs or evident tibial dyschondroplasia, x-ray-inspection–based subclinical or incipient development of tibial dyschondroplasia, curly or crooked toes or bowed legs, oxygen content of blood, and female's antibody titer to infectious bursal disease virus at 27 wk. Association analyses were conducted with allele and haplotype substitution effect models using progeny mean data adjusted for fixed and mate effects as sire trait records. Ten of the 12 genes had SNP associations with at least 1 trait. Most detected effects were with mortality and growth traits. Most gene–SNP trait associations varied by genetic line or with environment. These results indicate that associations of candidate genes with important broiler traits can be identified in multiple environments, and they offer a potential for the implementation of marker-assisted selection for traits expressed in the environment in which the commercial broiler needs to perform. The effects of these immune-related candidate genes, however, are complex and affected by genetic background and environment.