ABSTRACT: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic condition characterized by pain, pressure, and discomfort in the pelvic region coupled with urinary symptoms. The pain involved in IC/BPS can be debilitating and is incurable. As it stands, many of the available treatments for IC/BPS lack strong evidence for their use and are costly to patients. Further, patients report significant dissatisfaction with medical care, describing treatments as “trial-and-error," expensive, and having “fragmented” treatment plans to follow. Treatment advances in IC/BPS have stalled due to a lack of clear understanding of the condition, as symptoms and presentations vary widely. For these reasons, national organizations have prioritized the need to improve both treatment options and understanding of IC/BPS. Leading multi-institutional research networks have now identified that individuals with IC/BPS have distinct subgroups, or “phenotypes,” largely characterized by the distribution of pain throughout the body. These presentations of IC/BPS have distinct clinical and neurobiological features. Specifically, while a proportion of individuals with IC/BPS have symptoms primarily in the pelvic region (“peripheral” phenotype), others experience additional pain outside of the pelvis coupled with unrefreshing sleep, cognitive dysfunction, emotional distress, and energy depletion (“centralized” phenotype). In terms of neurobiological features, individuals with “centralized” presentations also exhibit exaggerated inflammatory responses to ex vivo stimulation and heightened responses to evoked pain. Supported by our preliminary evidence, the overall goal of this project is to assess how IC/BPS phenotype may affect response to two different therapies often given without regard to patient phenotype, pelvic floor physical therapy (PT) and cognitive-behavioral therapy (CBT) for IC/BPS. We hypothesize that we can predict those who will respond preferentially to either form of treatment based on reported bodily pain distribution (pelvic pain primarily, pain outside of the pelvis). We are proposing a randomized mechanistic trial to evaluate which participants may benefit from each treatment (Aim 1) and evaluate whether neurobiological mechanisms may moderate outcomes and change with treatment (Aim 2). Per an individual’s reported level of baseline widespread pain, we will randomize 220 participants to receive either 8-weeks of CBT or 10-weeks of PT. Participants will receive three assessments throughout, [before, after, and at 6- months]. Assessments include patient-reported outcomes, biological markers of inflammation, and psychophysical testing [taken at each timepoint]. This project has great potential to tailor treatment and improve future IC/BPS precision-medicine care efforts.