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Simple Summary: We have discovered that immunoglobulins digested with plasmin, one of the enzymes of blood clotting cascade acquire a capability to bind to one of the chains of plasminogen. We investigate here the mechanisms and localization of such binding. We also show that levels of this digested immunoglobulin molecule are higher in patients with prostate cancer. Therefore, this digested immunoglobulin could serve as a biomarker for the detection of patients with prostate cancer from patients with benign prostate hyperplasia. We observed that the diagnostic accuracy of blood levels of digested immunoglobulins is dramatically higher than that of PSA. The differential diagnosis of prostate cancer is problematic due to the lack of markers with high diagnostic accuracy. We previously demonstrated the increased binding of IgG to human plasminogen (PLG) in plasma of patients with prostate cancer (PC) compared to healthy controls. Heavy and light chains of PLG (PLG-H and PLG-L) were immobilized on 96-well plates and the binding of IgG to PLG-H and PLG-L was analyzed in serum from 30 prostate cancer (PC) patients, 30 patients with benign prostatic hyperplasia (BPH) and 30 healthy controls using enzyme-linked immunosorbent assay (ELISA). Our results demonstrate that IgG from PC sera bind to PLG-H but not to PLG-L. This interaction occurred through the free IgG C-terminal lysine (Lys) that becomes exposed as a result of IgG conformational changes associated with proteolysis. Circulating levels of modified IgG with exposed C-terminal Lys (IgG-Lys) were significantly higher in PC patients than in healthy controls and in BPH. We used Receiver Operating Characteristic (ROC) analysis to calculate the sensitivity (SN) and specificity (SP) of circulating IgG-Lys for differentiating PC from BPH as 77% and 90%, respectively. The area under the curve (AUC) was 0.87. We demonstrated that the diagnostic accuracy of circulating levels of IgG-Lys is much higher than diagnostic accuracy of total PSA (tPSA). [ABSTRACT FROM AUTHOR]