341 Background: Perineural invasion (PNI) is generally accepted as a major route of cancer dissemination encountered in malignancies associated with highly enervated organs. However, the effect of cancer cells on the blood vessels nourishing the nerves (i.e., vasa nervorum) remains unknown. Methods: We used immunohistochemistry involving three specific antibodies that recognize different endothelial markers (CD34, VEGF-R2 and FSHR), and standard histochemical methods (HES, PAS, TRICHROM) to detect changes in the vasa nervorum of nerves invaded by cancer cells in tissue samples from 85 patients diagnosed with locally advanced prostate cancer (LAPC). Genes known to be implicated in the process of angiogenesis and vascular remodeling have been also explored. NanoString nCounter Analysis covering 86 target genes was used for comparison of gene expression levels between LAPC (6 frozen samples) and normal prostate (NP; 2 frozen samples). Results: The percentage of the area occupied by CD34-positive vasa nervorum endothelial cells associated to nerves with PNI was significantly higher than that in nerves without PNI (6.93 ± 1.08 versus 1.76 ± 0.32; p = 0.003), suggesting a process of angiogenesis. In 18/85 (21%) of patients diagnosed with LAPC the vasa nervorum arterioles had a thick (25 ± 5 µm) tunica media consisting of collagen fibers. More than 75% of CD34-positive vasa nervorum of nerves with or without PNI expressed FSHR. In contrast, none of vasa nervorum expressed detectable VEGF-R2. A panel of 19 genes was found to be significantly (p < 0.05), differentially expressed between LAPC and NP. Six of them (ANGPT1, ITGB3, PGGFB, VEGFC, FSHR, and SDC1) have previously been associated with tumor progression, angiogenesis, and metastasis. Other three genes (SELE, SELP, and ESAM) are known to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. Conclusions: Perineural invasion of cancer cells caused angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.