To investigate the diagnostic potential of plasma miR-21 and miR-375 by comparing their levels in prostate cancer (PCa) patients to subjects without cancer in a Chinese population. The study population included 57 PCa patients and 28 benign prostatic hyperplasia (BPH) patients. The plasma levels of miR-21 and miR-375 were quantitated with Taqman based quantitative real-time polymerase chain reaction. In the BPH group, the median relative expression levels of miR-21 and miR-375 were 0.07 and 0.55, respectively; In the PCa group, the median values of miR-21 and miR-375 were 1.32 and 1.74, respectively. Both miR-21 (p=0.014) and miR-375 (p=0.005) plasma levels were significantly higher in PCa group than in BPH group. Using ROC analysis the AUC of miR-21 was 0.799, 95% CI between 0.690 and 0.908 (p=8×10 -6 ); for miR-375, the AUC was 0.757, 95% CI between 0.640-0.874 (p=0.000126). The largest AUC (0.881) was obtained when the data of miR-21, miR-375 and PSA were combined, with a sensitivity of 87.7% and a specificity of 75%. The results of this study showed that circulating miR-21 and miR-375 can discriminate PCa patients from BPH controls at early stages. Combinations of the studied miRNAs and PSA remarkably increased specificity compared with PSA alone. The combination method has the potential to be used as a noninvasive diagnostic cocktail for PCa screening.