Purpose Neuroinflammatory mechanisms are associated with fatigue in neurodegenerative conditions such as Parkinson’s. The symptoms in Parkinson’s including fatigue are thought to be related to α-synuclein overexpression. This study investigated genomic correlates of fatigue experienced by men with prostate cancer receiving external beam radiation therapy (EBRT). Patients and Methods Sixteen men with non-metastatic prostate cancer who were scheduled to receive EBRT were enrolled. Fatigue scores and blood were obtained at baseline (prior to EBRT, D0); one hour following initiation of EBRT (D1), day 7 (D7), day 14 (D14), midpoint (days 19–21, D21), completion (days 38–42, D42), and four weeks post EBRT (days 68–72, D72). Gene expression profiling using microarray analysis was performed from whole blood and confirmatory qPCR and protein (ELISA) analyses verified the microarray results. Correlations between fatigue and gene/protein expressions were determined using a mixed model approach. Results Microarray data showed significant, differential expression of 463 probesets following EBRT. SNCA had a 2.95 fold change at D21 from baseline. SNCA expression was confirmed by qPCR (p < 0.001) and ELISA (p < 0.001) over time during EBRT. Fatigue scores were significantly correlated with SNCA gene expression on D14 (r = 0.55, p < 0.05) and plasma α-synuclein concentrations on D42 of EBRT (r = 0.54, p = 0.04). Conclusion Fatigue experienced during EBRT may be mediated by α-synuclein overexpression. Alpha-synuclein may serve as a useful biomarker to understand the mechanisms and pathways related to the development of fatigue in this population.