Objective <p>This study aimed to investigate the expression and clinical significance of interleukin-27 (IL-27) and forkhead box P3 (Foxp3) in oral squamous cell carcinoma (OSCC) tissues, analyze their co-expression correlations, and explore their potential as prognostic biomarkers and therapeutic targets for OSCC.</p> Methods <p>Immunohistochemistry (IHC) was used to detect the expression of the two subunits of IL-27, IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), and Foxp3 in OSCC tissues and normal tissues. Chi-square test was used to analyze the correlation between the expression of the three in OSCC tissues and the clinical pathological parameters of patients.</p> Results <p>The IHC results showed that the expressions of IL-27p28, EBI3 and Foxp3 proteins in OSCC tissues were all higher than those in normal control tissues(<i>P</i>&lt;0.05); Correlation analysis indicated that IL-27 was associated with the presence or absence of lymph node metastasis in OSCC patients, and Foxp3 was related to the clinical stage of the tumor(<i>P</i>&lt;0.05). Their expressions were not related to the patients’ age, gender, primary tumor status, degree of differentiation, lesion location, or postoperative recurrence (<i>P</i>&gt;0.05).</p> Conclusion <p>The expression levels of IL-27p28, EBI3 and Foxp3 in OSCC tissues are significantly upregulated, indicating that the three play important roles in the occurrence and development of OSCC tumors. Furthermore, its high expression is associated with various clinicopathological characteristics of OSCC patients and can be used as a potential indicator for evaluating the prognosis of OSCC patients.</p>