Paclitaxel administration induces neuroinflammation that produces neurotoxicity and consequently determines the development of Chemotherapy-Induced Peripheral Neuropathy (CIPN) in animal models. We have identified X-box binding protein 1 (XBP1) as a major contributor to the inflammatory phenotype adopted by immune cells upon exposure to paclitaxel, and its blockade results in the reduction of CIPN-related pain behaviors. We propose to use our results using animal-based in vivo and in vitro systems to evaluate the translational potential of XBP1-dependent inflammatory molecules to determine CIPN disease severity. First, we identified key XBP1-dependent inflammatory cytokine signaling pathways using mouse macrophages exposed to paclitaxel and bulk RNA sequencing. Second, we conducted a correlative analysis of circulating inflammatory molecules with CIPN severity in cancer patients treated with paclitaxel-based chemotherapy. Our study recruited patients newly diagnosed with gynecologic malignancy receiving Paclitaxel-based first-line therapy before treatment initiation. Blood samples were collected before treatment and at each paclitaxel cycle. Serum paclitaxel levels were assessed by mass spectrometry, XBP1s mRNA levels in peripheral blood mononuclear cells (PBMCs) were measured by qPCR, and serum cytokine concentrations were quantified by ELISA multiplex assays. Clinically, the degree of CIPN was determined at every treatment cycle time point by an advanced provider based on CTCAE (Common Terminology Criteria for Adverse Events) grading criteria (scored 0-5, with 0 being asymptomatic and higher numbers indicating worse neuropathy). The final study cohort consisted of 9 female patients, mean age of 55 ± 17 years. All 9 received PTX/carboplatin, with 7 eventually developing CIPN. There was a significant association between the concentration of TNFa and neuropathy CTCAE grade (R2=0.72, r=0.83, P=0.008). Patients with higher levels of TNFa and greater CIPN grade displayed higher expression of XBP1s mRNA (P=0.08). XBP1s mRNA reached maximum levels, often preceding or coinciding with the development of CIPN. These results demonstrate that a greater level of TNFa correlated with the severity and timing of PTX-induced CIPN.