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Prostate cancer (PCa) is common world-wide. Current diagnostics based on testing for circulating levels of prostate specific antigen (PSA) is unspecific, and novel prognostic markers are needed for personalized therapeutic strategies. Pro-neuropeptide Y (pro-NPY) has been reported as a tissue marker for PCa related to poor prognosis. This study explored the prognostic value of circulating pro-NPY in PCa. Plasma samples were obtained from two patient cohorts: (1) men examined due to increased PSA levels in 2003–2011 (n = 796) and (2) patients treated for PCa in 2013–2016 (n = 92). Cohort 2 also provided plasma samples collected ~ 3 months after therapy. For plasma pro-NPY assessment, a sandwich immunoassay was developed. In cohort 1, 315 patients were diagnosed with PCa at the time for blood sampling, 137 were diagnosed during follow-up, and 344 remained disease-free. Plasma pro-NPY provided independent prognostic information from PSA regarding time to metastasis and PCa death. In cohort 2, high plasma pro-NPY levels were confirmed associated with metastatic disease and poor survival. Plasma pro-NPY levels were normalized after androgen-deprivation therapy, suggesting androgen-regulation. In conclusion, high circulating pro-NPY levels are associated with metastasis and poor outcome in PCa. Prospective validation is needed before suggesting pro-NPY for clinical use. The underlying biology and consequences of pro-NPY overexpression remain to be understood.