Vascular endothelial growth factor (VEGF) and the pigment epithelium-derived factor (PEDF) serve an important role in prostate cancer (PCa). The aim of the present study was to evaluate whether the levels of VEGF and PEDF in serum are associated with the severity of PCa, and whether they can differentiate from patients with benign prostatic hyperplasia (BPH). Two groups of patients were recruited, patients with PCa or BPH that were newly diagnosed without other comorbidities, and were compared with healthy individuals. The levels of VEGF and PEDF were measured by ELISA in serum, and by immunohistochemistry in biopsies. A correlation analysis was performed for the values in biopsies and serum, comparing the VEGF/PEDF ratio, total-prostate-specific antigen (t-PSA) levels and the status of each sample as acinar Ad (Gleason score) or as benign hyperplasia. The results demonstrated that serum levels of VEGF, PEDF, and t-PSA between PCa and BPH were similar to each other, but different to healthy individuals (P<0.05). The VEGF/PEDF ratio in serum had a significant difference between acinar Ad with Gleason score 8–10 and BPH groups (P<0.05). The VEGF and PEDF immunostaining intensities were correlated with its circulating levels in all cases of PCa, but not in BPH. These preliminary results suggest that VEGF and PEDF levels by themselves or in combination with t-PSA did not differentiate between malignant, and benign prostate diseases. However, there was a significant difference observed in the VEGF/PEDF ratio in serum between the groups, suggesting that it may be used as an index for diagnosis and prognosis in a personalized manner, although more studies are necessary.