['Cancer-related fatigue (CRF) is associated with negative health outcomes and decreased health-related quality of life; however, few longitudinal studies have investigated molecular-genetic mechanisms of CRF.', 'The objective of this study was to describe relationships between mitochondria-related gene expression changes and self-reported fatigue in prostate cancer patients receiving external beam radiation therapy (EBRT).', 'A prospective, exploratory, and repeated-measures design was used. Self-report questionnaires and peripheral whole-blood samples were collected from 15 patients at 7 time points. Baseline data were compared against 15 healthy controls. The Human Mitochondria RT Profiler PCR Array was used to identify differential regulation of genes involved in mitochondrial biogenesis and function.', 'Compared with baseline, there were significant increases in fatigue scores (P = .02-.04) and changes in mitochondria-related gene expression (P = .001-.05) over time. Mean fatigue scores were 1.66 (SD, 1.66) at baseline, 3.06 (SD, 1.95) at EBRT midpoint, 2.98 (SD, 2.20) at EBRT completion, and 2.64 (SD, 2.56) at 30 days after EBRT. Over time, 11 genes related to mitochondrial function and structure were differentially expressed. Of these 11 genes, 3 (BCL2L1, FIS1, SLC25A37) were more than 2.5 fold up-regulated, and 8 (AIFM2, BCL2, IMMP2L, MIPEP, MSTO1, NEFL, SLC25A23, SLC25A4) were greater than 2-fold down-regulated. Furthermore, 8 genes (AIFM2, BCL2, FIS1, IMMP2L, MSTO1, SLC25A23, SLC25A37, SLC25A4) were significantly associated with the changes in fatigue scores.'] Are mitochondria-related gene expression changes associated with fatigue in patients with nonmetastatic prostate cancer receiving external beam radiation therapy?