Abstract Prostate tumors are highly heterogeneous and molecular characterization based on biopsy sampling is often challenging. Hence, it is desirable to have an easily accessible, minimally invasive way to determine the molecular imprints of a patient’s tumor. Exosomes in blood are an important source of non-invasive, circulating biomarkers and provide an enriched source of microRNAs. With an objective of identifying microRNA based markers, we developed a comprehensive procedure for exosomal microRNA profiling analyses from sera of prostate cancer patients employing Nanostring nCounter technology. In a pilot study, we profiled exosomal miRNAs from a training cohort of normal individuals, patients with benign prostate hyperplasia (BPH), indolent form of PCa and aggressive metastatic prostate cancer. Exosomes were extracted from serum and the integrity of exosomal preparations was confirmed by nanoparticle tracking analysis and Western blot analyses for exosomal markers CD63, CD9 and TSG101. Levels of two miRNAs were significantly upregulated and several candidate miRNAs were markedly downregulated in metastatic PCa serum samples compared with controls. The candidate microRNAs were further validated in a larger cohort by real time PCR based microRNA assays. Of significance, we validated miR-1246 as an exosomal marker for prostate cancer. miR-1246 levels were specifically altered in prostate cancer patients and not significantly altered in BPH. Our analyses suggest that miR-1246 is a promising diagnostic biomarker for prostate cancer. Citation Format: Divya Bhagirath, Thao Yang, Kirandeep Sekhon, Nathan Bucay, Shahana Majid, Yutaka Hashimoto, Priyanka Kulkarni, Pritha Dasgupta, Marisa Shiina, Varahram Shahryari, Mitsuho Imai-Sumida, Soichiro Yamamura, Z Laura Tabatabai, Yuichiro Tanaka, Rajvir Dahiya, Guoren Deng, Sharanjot Saini. An exosomal biomarker for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5448. doi:10.1158/1538-7445.AM2017-5448