This study was designed to investigate whether Foxp3( +) regulatory T (Treg) cells play a role in the histopathologic changes of primary Sjögren's Syndrome (pSS) and to evaluate other factors possibly associated with Foxp3(+) Treg cells in pSS patients. The number of FoxP3-expressing T cells in peripheral blood (PB) of 39 patients with pSS, 40 patients with rheumatoid arthritis (RA), and 28 healthy controls was measured by flow-cytometer analysis. FoxP3-expressing CD4(+)CD25(+) Treg cells were analyzed in minor salivary gland (SG) tissues of 39 pSS patients. Histopathologic changes were examined by light microscopy according to Chisholm's classification. Immunohistochemistry and immunofluorescence were performed to assess the Foxp3(+) Treg in SG biopsy specim-ens. The numbers of CD4(+) T cells and FoxP3-expressing CD4(+) T cells in PB were similar in all groups. Expression of CD25 on CD4(+) T cells in PB of patients with pSS and RA was significantly higher than in healthy controls, especially for RA patients. Immunohistochemistry and immunofluorescence showed that FoxP3(+) Treg were enriched in the SGs of pSS patients, with a positive correlation between the increase in FoxP3(+) Treg in SG and the Chisholm score in pSS (p < 0.001, r = +0.605). The increase of FoxP3( +) Treg cells in the SGs of pSS patients, which is correlated with gland infiltration, suggests that natural regulatory T cells play an important role in the pathogenesis of pSS. Further studies are required to explore the mechanisms that mediate the relationship between Treg and the pathogenesis of pSS.