Oxidative stress (OS) has been associated with aging and age-related diseases in humans, as well as with the decline in economic trait performance in poultry and other domesticated animals. However, the potential effects of OS on the poultry immune system are not well understood. In addition, the impact of bird genetic variation on redox balance remains to be elucidated. Thus, the central hypothesis of this dissertation is: The bird’s adaptive immunocompetence is impacted by their OS level, which is not only influenced by environmental factors, but also related to genetic phenotype of either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). In the first phase of this study, White Leghorn chickens were provided ethanol at different concentrations in drinking water to induce OS. Biomarkers including malondialdehyde (MDA), glutathione (GSH), and plasma uric acid (PUA) were measured to assess OS before and after ethanol treatment. The adaptive immune response during an OS event was measured by plasma IgG and IgM levels, major lymphoid organ weights, CD4+/CD8+ cell ratio, and histopathological analysis of the immune organs. Results showed that when OS was induced by 10% ethanol, chicken adaptive immune responses decreased; however, when birds were exposed to 2% ethanol, there was an enhancement in antioxidant defense and immune response; These results would suggest a negative correlation between OS level and chicken adaptive immune response. In the second phase of the study, subsets of chickens were selected based on their high (H)- or low (L)-OS to assess for variations in their genetic phenotypes. Using MDA levels, 36 chickens were chosen to scan a 2734-bp region of mtDNA, but no definitive SNP was detected. In another experiment, 40 chickens were conversely selected according to three biomarkers for OS. Although no variation was found at eight SNP loci tested across the mitochondrial genome, mtDNA damage measured by 8-hydroxy-2’-deoxy-guanosine was shown to increase with time, and at higher levels in the high OS birds (p < 0.05). Thses results suggest that long-term high OS levels in chickens may increase the somatic mutation of their mtDNA. In the final phase of this dissertation, the effect of nDNA on OS, measured via a genome-wide association study was performed with 18 H and 18 L chickens using the latest chicken 60k SNP microarray for genotyping. Among 56,483 SNPs successfully genotyped, 13 SNPs across five independent loci were associated with OS at significance level of p ≤ 0.001, and another 144 SNPs were also associated with OS (p ≤ 0.01). These results indicate new loci and related genes for their genetic influence upon redox balance. In general, experiments carried out on White Leghorn chickens here have shown that adaptive immune response is tightly related to changes of OS. Further, genetic variance in nDNA is associated with the risk of high OS or the ability to better resist it.