Bortezomib (BTZ) is an antineoplastic drug that reversibly binds to an active site threonine in the 26S proteasome. The inhibition of protein degradation in the cells leads to the accumulation of signalling molecules, blocking the tumour survival pathways. BTZ is mainly used for the treatment of multiple myeloma, but unfortunately its clinical use have evidenced the onset of a painful peripheral neuropathy (BIPN) that decreased patients’ quality of life. Despite the clinical relevance of BIPN, our knowledge of the molecular mechanism underlying the painful condition is still limited. In recent studies, inflammation has been described as a possible event in the onset of neuropathic pain induced by some chemotherapy drug. To investigate the putative role of immune response in the BTZ-induced painful peripheral neuropathy, we defined a new immune-suppressed murine model based on sub-lethal X-ray irradiation. Adult female BALB/c mice underwent X-ray irradiation, once a week for 4 weeks with a first dose of 350 RAD and 3 subsequent 100 RAD doses (X-ray group), to deplete the immune cells-mediated response. Part of these animals were treated with BTZ 0.8 mg/kg twice a week for 4 weeks (X-ray+BTZ group). To assess the BTZ-induced neurophysiological damage and the onset of neuropathic pain, nerve conduction velocity and mechanical nociceptive threshold were measured. Sciatic nerve, spinal cord and dorsal root ganglia were processed for light microscope observations. Moreover, flow cytometer analysis of CD45-positive cells were performed in tibiae bone marrow (BM) and peripheral blood (PB) to confirm the immune-suppression. After the first X ray irradiation piloerection and hypokinesia were observed, and significant body weight decreased was measured at the end of treatment in X-ray+BTZ-treated animals. The immune-suppression was persistent in the PB until the end of the study, while a partial recovery in BM was observed in the last time-point evaluation. In addition, BTZ induced the onset of the mechanical allodynia after the beginning of treatment and an impairment of nerve functions in both caudal and digital nerves. X ray irradiation per se was not able to induce any neurophysiological change. Further investigations are required to deeply understand the role of inflammation in the pathogenic mechanism of BTZ-induced painful peripheral neuropathy, and to identify novel therapeutic targets for an effective therapeutic approach. Supported in part by a research grant from the University of Milano-Bicocca F.A.R.