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Background: Prostate cancer (PCa) is one of the most common malignant tumors of the male urinary system, and its incidence and mortality rates have been increasing worldwide. Benign prostatic hyperplasia (BPH) represents stromal and epithelial cell proliferation in the prostate in elderly males. Abnormal activation of inflammation-related signalling molecules, such as toll-like receptor 4 (TLR4) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) has been linked to the initiation and progression of various human diseases including PCa and BPH. Cylindromatosis (CYLD) gene alterations are associated with PCa progression. In this study, the contribution of CYLD, JAK2, and TLR4 gene variants to PCa and BPH risks and their associations with prostate-specific antigen (PSA) levels, immunophenotype, and clinical features in Vietnamese men were determined. Methods: A total of 102 patients with PCa, 65 with BPH, and 114 healthy controls were enrolled. The immunophenotype was analyzed by flow cytometry, cytokine secretion by enzyme-linked immunosorbent assay (ELISA), and gene variants by DNA sequencing. Results: Lower levels of transforming growth factor β (TGF-β) and higher numbers of CD13+CD117- and CD56+CD25+ cells were observed in the PCa group than in the BPH group. Genetic analysis of the CYLD gene identified five single nucleotide polymorphisms (SNPs), of which c.2351-47 C>T, c.2351-46A>T, and rs1971432171 T>G had significantly higher frequencies in PCa patients than in the control and BPH groups. Sequencing of the TLR4 gene revealed five nucleotide changes, in which the rs2149356 SNP showed an increased risk for both PCa and BPH and the c.331-206 SNP had a reduced risk for PCa. Importantly, the expansion of activated natural killer (NK) cells and higher levels of PSA were found in PCa patients carrying the CT genotype of the CYLD c.2351-47 compared to those with the wild-type genotype. Conclusion: Activation of NK cells in CYLD-sensitive PCa patients was associated with serum PSA release and the CYLD c.2351-47 variant may be a significant risk factor for prostatitis in PCa patients.