Objective: The objective of this study was to investigate the potential role of Toll-like receptor 9-dependent p38 MAPK signaling pathway in the pathogenesis of primary Sj(o)gren s syndrome in NOD/Ltj mouse, aiming to identify an ideal target therapy model for human primary Sj(o)gren's syndrome.Methods: NOD/Ltj mice were chosen as a model of primary SjSgren's syndrome.The Toll-like receptor 9 and p-p38 MAPK double positive peripheral blood mononuclear cells of 4, 5, 8, 10, 15-week-old NOD/ Ltj mouse were analyzed by flow cytometry.The expressions of Toll-like receptor 9 and p-p38 MAPK in the submandibular gland were also examined by immunohistochemistry.The change of stimulated salivary flow rate was dynamically measured and the histopathology of submandibular gland was evaluated by hematoxylin and eosin stain.Results: The stimulated salivary flow rate in NOD/Ltj was reduced to 50%~60% of the flow rate of control mice since the fifth week onwards.The Toll-like receptor 9 and p-p38 MAPK double positive peripheral blood mononuclear cells in both groups increased gradually from 5 weeks, peaked at 8 weeks and then gradually decreased at 10 weeks, yet the percentage of Toll-like receptor 9 and p-p38MAPK double positive peripheral blood mononuclear cells in 5, 8, 10-week-old NOD/Ltj mouse was significantly increased compared with those in control subjects.After the tenth week onwards, there were no significant difference in the Toll-like receptor 9 and p-p38 MAPK double positive peripheral blood mononuclear cells between NOD/Ltj mice and controls.Immunohistochemical staining showed that Toll-like receptor 9 were positive in the acinar epithelium cells and infiltrating lymphocytes in NOD/Ltj mice.P-p38 MAPK was detected in infiltrating lymphocytes and few ductal or acinar epithelium cells adjacent to infiltrating lymphocytes in NOD/ Ltj mice.Conclusions: From the fifth week till the tenth week, Toll-like receptor 9 and p-p38 MAPK double positive peripheral blood mononuclear cells were significantly increased in NOD/Ltj mice, accompanied with reduced stimulated salivary flow rate and Toll-like receptor 9 or p-p38 MAPK positive infiltrating lymphocytes observed in the submandibular gland of NOD/Ltj mouse.Our results indicated that activation of Toll-like receptor 9-depended p38 MAPK signal pathway in peripheral blood mononuclear cells was an early event in primary Sj(o)gren's syndrome which made NOD/Ltj as an ideal therapy model to test the treatment effects of p38 MAPK or Toll-like receptor 9 inhibitors on primary Sj(o)gren's syndrome.