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Background Cancer Related Fatigue (CRF) is one of the most prevalent and distressing symptoms associated with cancer treatments. The exact etiology of CRF and its mechanisms are poorly understood. Cytokine dysregulation was hypothesized to be one of these mechanisms. Here, we explored the associations of soluble and extracellular vesicle (EV)-associated markers that include cytokines, heat shock proteins (hsp27, hsp70, hsp90), and neurotrophic factors (BDNF) with CRF. Methods Plasma was collected from men (n ​= ​40) with non-metastatic prostate cancer receiving external beam radiation therapy (EBRT) at the start of the treatment, and three months after EBRT. CRF was assessed using the Functional Assessment of Cancer Therapy - Fatigue (FACT-F) from all participants. EVs were characterized via Nanoparticle Tracking Analysis, electron microscopy, and Western blot. Concentrations of EV-associated and soluble markers were measured with a multiplexed immunoassay system. Bivariate correlation analyses and independent T tests analyzed the relationships of CRF with the markers. Findings As CRF worsened, concentrations of EV-associated markers were upregulated. EV-associated fold changes of Eotaxin, hsp27, IP-10, MIP-3α, were significantly higher in fatigued participants compared to non-fatigued EBRT participants three months after treatment. This was not observed in soluble markers. Concentrations of EV-associated CRP and MCP-1, soluble survivin, IFNα2, IL-8, IL-12p70, and MCP-1 significantly correlated with lower (worsening) CRF scores at the start of and three months after treatment. Interpretation Concentrations of EV-associated markers increased in fatigued men with prostate cancer three months after EBRT. Both EV-associated and soluble markers correlated with worsening CRF. EV-associated markers, which have not been previously studied in depth, may provide additional insights and serve as potential biomarkers for CRF., Highlights • Cancer-related fatigue is associated with the increase of soluble and extracellular vesicle-associated cytokines. • Increase in vesicle-associated immune markers is associated with worsening cancer-related fatigue. • Both soluble and vesicle-associated immune markers can serve as biomarkers for cancer-related fatigue.