Background: The mediator complex plays a pivotal role in the regulation of gene transcription. The subunits CDK8 and CDK19 are overexpressed in advanced prostate cancer (PCa) and promote migration and invasion, as shown previously by our group. The aim of this study was to analyze if CDK8/CDK19 inhibition can impede PCa progression. Methods: Immunohistochemistry for CDK8 and CDK19 was performed on a large PCa cohort (376 radical prostatectomy (RP) specimens, 39 locally advanced tumors, 32 lymph node metastases, 24 distant metastases, 73 benign prostatic specimens). PCa cell lines (DU145, PC3) were treated with CDK8/CDK19 small molecule inhibitors followed by MTT assay, wound healing assay, and Western Blot for epithelial/mesenchymal markers. Results: CDK19 is higher expressed in primary PCa vs. benign specimens and locally advanced PCa/distant metastases vs. primary PCa. CDK8 and CDK19 are higher expressed in castration-resistant specimens vs. hormone-naive specimens. CDK19 significantly correlates with grade group in RP specimens. Biochemical recurrence free survival rates are lower for patients with high vs. medium vs. no/low CDK19 expression in the tumor. CDK19 predicts recurrence free survival independently from grade group and PSA. CDK8/CDK19 inhibition results in decreased migration, while there is no effect on proliferation. Mesenchymal markers are reduced while epithelial markers are induced following CDK8/CDK19 inhibition. Conclusions: CDK19 qualifies as a prognostic marker predicting biochemical recurrence following RP. CDK8/CDK19 inhibition leads to decreased migratory potential and mesenchymal phenotype. CDK8/19 expression increases during progression to castration-resistance. Collectively, CDK8/CDK19 represents a new target for treatment of advanced and/or castration-resistant PCa.