Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent malignancies in the head and neck region, with a high morbidity rate and a poor prognosis. As a result, the search for effective biomarkers to assess OSCC's prognosis has become a research hotspot. Given that the impact of Forkhead box protein P3 (FOXP3) as a significant marker of regulatory T cells (Tregs) on OSCC's prognosis remains a subject of debate, the current study was carried out to elucidate FOXP3 importance in the prognostic assessment of OSCC patients.

Methods: Four major databases, i.e., Web of Science, Embase, Cochrane Library, and PubMed, were searched for relevant articles up to 10 February 2025. The 95% confidence intervals (95% CIs) and hazard ratios (HRs) reported in the selected articles were extracted and combined for analysis. The primary outcome was overall survival (OS), while the secondary outcomes encompassed recurrence-free survival (RFS), disease-specific survival (DSS), and disease-free survival (DFS). These outcomes were pooled and analyzed using Stata 15.

Results: 19 articles were included, comprising a total of 2136 patients. The findings revealed that high FOXP3 did not have a significant association with OS under the random-effects model analysis (HR = 0.96, 95% CI = 0.60–1.54, p = 0.88) but had a significant association with DSS under the fixed-effects model analysis (HR = 0.55, 95% CI = 0.44–0.67, p < 0.001). The heterogeneity was within an acceptable range (I² = 29.3%, p = 0.175). High FOXP3 was not significantly correlated with either DFS or RFS.

Conclusions: High expression of FOXP3 is significantly associated with improved DSS in OSCC. However, due to inconsistent relationships with other survival outcomes, its clinical application potential requires further validation.

Systematic Review Registration PROSPERO (CRD420250651264).