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Simple Summary: Metastatic castration-resistant prostate cancer (mCRPC) represents a lethal stage of prostate cancer, characterized for its resistance to androgen deprivation therapy and variable survival outcomes. This study investigates how the composition of specific immune cells in the blood affects the prognosis of mCRPC patients who have not yet received chemotherapy. In looking at blood samples taken before treatment with the drug enzalutamide, we discovered significant correlations between lower levels of CD8 T cells and higher levels of monocytes, which were consistently linked to poorer survival rates. The prognostic value of blood CD8 T cells was independently validated in multivariate prognostic models and in an independent cohort of mCRPC patients. This study highlights the feasibility of blood immune-cell profiling in patients included in clinical trials and the association of blood CD8 T cells with the prognosis for mCRPC patients. The prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) varies, being influenced by blood-related factors such as transcriptional profiling and immune cell ratios. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. This study analyzed pre-treatment blood samples from 152 chemotherapy-naive mCRPC patients participating in a phase 2 clinical trial (NCT02288936) and a validation cohort. We used CIBERSORT-X to quantify 22 immune cell types and assessed their prognostic significance using Kaplan–Meier and Cox regression analyses. Reduced CD8 T-cell proportions and elevated monocyte levels were substantially connected with a worse survival. High monocyte counts correlated with a median survival of 32.2 months versus 40.3 months for lower counts (HR: 1.96, 95% CI 1.11–3.45). Low CD8 T-cell levels were associated with a median survival of 31.8 months compared to 40.3 months for higher levels (HR: 1.97, 95% CI 1.11–3.5). These findings were consistent in both the trial and validation cohorts. Multivariate analysis further confirmed the independent prognostic value of CD8 T-cell counts. This study highlights the prognostic implications of specific blood immune cells, suggesting they could serve as biomarkers in mCRPC patient management and should be further explored in clinical trials. [ABSTRACT FROM AUTHOR]