Background: In the US, 20-40% of men with localized prostate cancer fail primary therapy (surgery or radiation), as indicated by a subsequent rise in PSA. These patients are often treated with ADT to lower their PSA and delay the onset of metastatic disease. In addition, ADT has been shown to enhance anti-tumor immune responses and to augment various cancer immunotherapies. Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Sipuleucel-T is given as a series of 3 infusions and designed to induce an antigen-specific immune response against prostate cancer. Here, we propose a clinical trial combining ADT with sipuleucel-T that investigates the influence of treatment sequence on markers of immune response in non-metastatic prostate cancer patients with a rising PSA after primary therapy. The primary study objective is to determine which treatment sequence leads to a superior augmentation of immune markers: ADT started before or after sipuleucel-T. Secondary objectives include: the safety profile of sipuleucel-T in this patient population and the maintenance of immune markers over time. Methods: 60 subjects will be randomized (1:1) to receive sipuleucel‑T followed by ADT (given 2 wks after the 3^rd immunotherapy infusion), or ADT followed by sipuleucel-T (given 3 mo after ADT initiation). In both arms, ADT treatment will continue through Month 18. Patients will be stratified by 1) PSA doubling time (≤3 mo, >3 to ≤12 mo), and 2) radical prostatectomy (RP) or radiation therapy (XRT) or RP plus salvage XRT. Cellular and serological immune responses will be assessed before and after sipuleucel-T infusions 1, 2, and 3 and at the following time points after the 3^rd infusion: weeks 2, 6, 12 and months 6, 9, 12, 15, and 18. PSA and testosterone will be monitored every 3 months through Month 18. Immune marker responses will be compared between groups to determine the importance of ADT and sipuleucel-T sequencing.