Abstract Prostate specific antigen (PSA) screening is an established and useful tool for prostate cancer detection, however, it has no predictive prognostic value at diagnosis. For early diagnosed localized prostate cancer, the major clinical challenge is the treatment decision, in whether a patient should receive invasive intervention or be managed as “watchful waiting” active surveillance. Consequently, patients with indolent prostate cancer can be unnecessarily over-treated; or conversely, patients with prostate cancer of an aggressive nature may miss out on needed treatment, which ultimately leads to mortality. Therefore, it is an urgent need to develop prognostic biomarkers for localized prostate cancer to guide clinical decision making that is most beneficial to each patient. The objective of this proposal is to address the imminent clinical need by developing and validating a panel of potential prostate cancer prognostic biomarkers. Based on the literature and our compelling preliminary findings, we hypothesize that serum levels of the soluble NKG2D ligand MIC (sMIC) in combination with tumor-associated glycan profiles can provide the predictive biomarker capacity for prostate cancer prognosis. We have assembled large cohorts of prostate cancer tissues and matching serum collected from men diagnosed with localized prostate cancer at the time of prostatectomy. These samples have annotated clinical information including follow up PSA biochemical recurrence (BCR) status. These samples will be used to develop a unique panel of prognostic biomarkers and validate their specificity and sensitivity. Findings will be further validated with independent cohorts of serum samples from clinically-defined prostate cancer patients. There are four Specific Aims: 1) Determine the sensitivity and specificity of tissue MIC and serum sMIC in predicting BCR; 2) Determine the sensitivity and specificity of tissue and serum multi- fucosylated glycan panels in predicting BCR; 3) Determine the prognostic capacity of serum and tissue biomarker panel 4) Validate prognostic capacity of the identified panel of serum biomarkers with independent cohorts of patient samples. The proposed study will be accomplished through a collaborative effort led by a team of well-established investigators.