The study investigated how blood inflammatory markers combined with tumor markers can help distinguish benign prostatic hyperplasia (BPH) from prostate cancer (PCa), as both diseases have similar clinical manifestations and current biomarkers have limited specificity. A retrospective analysis included 200 men (53 with prostate cancer and 147 with BPH) comparing clinical characteristics, laboratory parameters, and inflammatory indices. Prostate cancer patients had significantly higher levels of inflammatory markers than BPH patients. In the analysis, log2-SII and log2-AISI were shown to be independent risk factors for prostate cancer. The AISI-based model achieved better diagnostic performance with an AUC of 0.878 compared to the SII model (AUC = 0.855). Inflammatory blood markers, especially AISI, in combination with conventional biomarkers offer increased diagnostic accuracy for distinguishing BPH from PCa and represent a non-invasive and cost-effective approach for clinical decision-making.