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Aim: The aim of the study was to observe the effect of acupuncture on regulating interleukin (IL)‐17, tumor necrosis factor (TNF)‐ɑ, and aquaporins (AQPs) in Sjögren's syndrome (SS) on patients and on non‐obese diabetic (NOD) models. Methods: Levels of anti‐AQP 1, 5, 8, and 9 antibodies, IL‐17, and TNF‐ɑ in the serum of SS patients were compared prior and following 20 acupuncture treatment visits during 8 weeks. While in murine model, five groups were divided to receive interventions for 4 weeks, including control, model, acupuncture, isoflurane, and hydroxychloroquine. The submaxillofacial gland index, histology, immunohistochemistry of AQP1, 5, salivary flow, together with IL‐17, and TNF‐ɑ expression in peripheral blood were compared among the groups. Results: Acupuncture reduced IL‐17, TNF‐ɑ, and immunoglobin A levels, and numeric analog scale of dryness in 14 patients with SS (p < 0.05). The salivary flow was increased, and the water intake decreased in NOD mice receiving acupuncture treatments. IL‐17 and TNF‐ɑ levels in peripheral serum were down‐regulated (p < 0.05) and AQP1, 5 expression in the submandibular glands up‐regulated in mice. Conclusion: The effect on relieving xerostomia with acupuncture may be achieved by up‐regulating the expression of AQP1. AQP5, down‐regulating levels of IL‐17 and TNF‐ɑ, and a decrease in inflammation of glands. [ABSTRACT FROM AUTHOR]