Background: Chemotherapy (CT) via inflammation and oxidative stress can cause muscle inflammatory injury, mitochondrial damage, and cancer-related fatigue (CRF). Following muscle and mitochondrial damage, various cytoplasmic and mitochondrial components are released into circulation. HLA-DQB1 gene encodes a protein involved in the activation of immune response, and is not expressed in normal muscle cells but is up-regulated under highly inflammatory states. Mitochondrial gene MT-CO2 encodes subunit 2 of complex IV, which plays a critical role in energy metabolism and mitochondrial function. We investigated the (i) influence of an exercise intervention, Exercise for Cancer Patients (EXCAP), on gene expression levels of muscle immune response and mitochondrial damage and (ii) the relationships of these genes with CRF. Methods: In this nationwide, multicenter, phase III RCT conducted through the URCC NCORP Research Base, cancer patients (N = 350; mean age = 55.7) were randomized to 2 groups: (i) CT and (ii) CT plus a 6-week individualized, home-based, aerobic and resistance exercise program (EXCAP). Gene expression and CRF were assessed pre- and post-intervention from whole blood by qPCR and from patient-report by MFSI, respectively. Results: T-tests revealed significant upregulation of peripheral HLA-DQB1 and MT-CO2 mRNA following CT in controls (both p < 0.00001) while there was less up-regulation in exercisers (both p≤0.005). ANCOVA showed a trend for significant differences between controls and exercisers for HLA-DQB1 (9.2% vs 5.4%; p = 0.059) and MT-CO2 (16.3% vs 12.7%; p = 0.061). Pearson correlations revealed that increases in HLA-DQB1 (r = 0.21; p = 0.051) and MT-CO2 (r = 0.19; p = 0.025) were significantly associated with concurrent increase in CRF in controls, but not in exercisers. Conclusions: CT alters muscle immune response and mitochondrial gene expression causing muscle and mitochondrial damage, which may be mediators for CRF. EXCAP is a promising intervention that may reduce both muscle and mitochondrial damage via its positive effects on HLA-DQB1 and MT-CO2. Funding: NCI UGCA189961, R25 CA102618.Clinical trial information: NCT00924651