Increasing evidence suggests that immune cell infiltration is involved in primary Sjögren's syndrome (pSS), while the underlying molecular mechanisms remain elusive. Herein, this study aims to explore the key molecular mechanism in immune cell infiltration in pSS based on Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained, followed by weighted gene co-expression network analysis to acquire the pSS-related module genes. Moreover, pSS-related DEGs and module genes were intersected. Additionally, the correlation between key genes and immune cell infiltration was analyzed by CIBERSORT algorithm. Furthermore, pSS mouse models were established to explore the effects of PSMC6 on immune cell infiltration and inflammatory responses in pSS. A total of 51 DEGs and 334 key module genes were involved in the occurrence of pSS. The immune cell infiltration was correlated with pSS, and PSMC6, highly expressed in pSS samples, may be the key immune gene. In vivo animal experiments demonstrated that PSMC6 was upregulated in pSS, and PSMC6 knockdown could reduce lymphocytic infiltration in salivary glands and lacrimal glands and the levels of related inflammatory factors in the pSS and increase the proportion of Treg cells. Collectively, PSMC6 could induce immune cell infiltration and inflammatory responses to promote the occurrence of pSS, providing us with a potential therapeutic target for treating pSS.