Marek's disease (MD) is a T-cell lymphoma of chickens induced by a herpesvirus, the Marek's disease virus. Since MD is a significant economic problem to the poultry industry, there is great interest in enhancing genetic resistance, which is controlled by multiple genes. MD is also a biomedical model, as vaccines prevent disease formation but do not prevent viral replication. The influence of the major histocompatibility complex has been clearly demonstrated, and several quantitative trait loci have been mapped; however, no single gene influencing MD resistance has been identified. Transcription of SORF2 is perturbed in the Marek's disease virus recombinant clone RM1 owing to a solo insertion of the reticuloendotheliosis virus long terminal repeat, which may explain the loss of oncogenicity for this strain. Hypothesizing that SORF2-interacting host proteins are involved in MD resistance, we screened a chicken splenic complementary DNA library by the yeast two-hybrid assay using SORF2 as bait. The chicken growth hormone structural peptide was identified and the specific interaction verified by co-immunoprecipitation. Immunohistochemical staining and indirect immunofluorescence assay indicated that growth hormone and SORF2 are expressed and can be co-localized in cells infected with the Marek's disease virus and MD tumors. Furthermore, depending on the major histocompatibility complex genotype, polymorphism in the growth hormone gene (GH1) is associated with the number of tumors in a commercial chicken resource population. We conclude that GH1 is likely to be an MD resistance gene. Furthermore, a systematic search of virus–host protein interactions should complement our quantitative trait loci scans and DNA microarrays to identify other resistance genes to MD.