This study investigated the role of interleukin (IL)-9 and IL-10 in the pathogenesis of chronic spontaneous urticaria (CSU). Autologous serum skin test and histamine release test were performed in CSU patients and normal subjects. Kunming mice were used to develop a mouse model for CSU. We induced IL-9 overexpression, IL-10 overexpression, and JAK/STAT pathway inhibition as well as a combination of all three conditions in CSU and control mice. Eosinophils in the skin tissues, inflammatory cytokine expression, and distribution of T lymphocyte subsets in peripheral blood of mice were detected. Expression patterns of IL-9, IL-10, STAT3, JAK2, and INF-γ in clinical samples and mice were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The positive rate of autologous serum skin test and the histamine release rate of CSU patients, compared with normal subjects, were apparently elevated. Compared with controls, mice with CSU experienced longer duration and higher frequency of pruritus and demonstrated enhanced levels of CD8 + , the ratio of CD4 + /CD8 + , number of eosinophils, and inflammatory cytokine expression in serum as well as activated JAK/STAT signalling pathway; at the same time, levels of CD4 + and INF-γ were reduced. This trend was found in CSU mice overexpressing IL-9 and IL-10 when compared with the CSU mice without treatment. In contrast, JAK/STAT inhibition reversed the above trend.Overall, our study suggests that IL-9 and IL-10 contribute to CSU development via activation of the JAK/STAT signalling pathway. K E Y W O R D S chronic spontaneous urticaria, inflammation, interleukin-9, interleukin-10, JAK/STAT signalling pathway 1 | INTRODUCTION Chronic urticaria (CU), defined as urticaria that has been continuously or intermittently existing for more than 6 weeks, has an estimated prevalence in the general population of 0.5% to 5% and an incidence of 1.4% per year. 1 Patients where no underlying cause for CU was identified were diagnosed as chronic idiopathic urticaria (mainly used in North America) or chronic spontaneous urticaria (CSU). 2 CSU is caused by degranulation of basophils and/or cutaneous mast cells, which results in effective vasoactive mediators released to induce vasodilatation and increased capillary permeability, leading to erythema and wheal formation. 3 Wheal is an elementary dermatological lesion, characterized by itchiness and the presences of central oedema in various sizes, with a reflex erythema encircling and ephemeral