BACKGROUND: Cutaneous neurofibroma (cNF) presenting with pain and itch substantially affects the quality of life. The CXCL10/CXCR3 axis, a well-known chemokine signaling pathway involved in pain and itch transmission, has recently been implicated in neurofibroma development. Our study aims to investigate the expression patterns and potential roles of the CXCL10/CXCR3 axis in pain and itch associated with cNFs. METHODS: We examined the expression of CXCL10/CXCR3 and immune cell profiles in 53 human solitary cNFs through immunohistochemical staining. The Chinese version of the Short-form McGill Pain Questionnaire and the Chinese Eppendorf Itch Questionnaire were used to assess pain and itch symptoms of cNF tumors, respectively. RESULTS: Elevated expression of CXCL10/CXCR3 was observed in tumoral and dermal parts of symptomatic cNFs. The percentage of mast cells expressing CXCL10, but not CXCR3, was significantly higher in symptomatic cNFs compared to asymptomatic cNFs (51.18% vs. 19.07%, respectively, p < 0.0001). The symptomatic cNFs exhibited significantly higher intraepidermal nerve fiber density compared to asymptomatic cNFs (p = 0.009). CONCLUSIONS: Our study suggests that CXCL10, potentially mediated by mast cells, may contribute to sensory dysfunction in cNF and may be a target for treating the pain and itch symptoms associated with cNFs. Our study suggests a model in which the CXCL10/CXCR3 pathway plays a role in inducing pain and itch in cNFs, potentially through mast cell mediation. Mast cells may increase the secretion of CXCL10, thereby contributing to pain and itch in cNF, making them a potential target for treating these symptoms. Created in BioRender. Pham, Q. (2025) https://BioRender.com/i89y356 .