Background: The interleukin-1 (IL-1) signaling pathway plays a crucial role in mediating inflammatory responses by activating immune cells, with implications for various pathologies. In oral squamous cell carcinoma (OSCC), the role of IL-1 receptor antagonist (IL-1RA) and its isoforms remains poorly understood, with evidence suggesting context-dependent variations in their function. Aim: This study aimed to evaluate the immunoexpression of IL-1 signaling pathway in OSCC tissues and correlate these findings with clinicopathological prognostic factors. Methods: Clinicopathological data, including patient age, sex, tumor size, lymph node involvement, histological grade, and tumor stage, were evaluated. Hematoxylin and eosin-stained sections were reviewed for differentiation grade, tumor budding, perineural invasion, and the presence of adequate tumor tissue in the invasive front. Non-dysplastic adjacent epithelium (NDAE) from the same samples served as the control. Immunohistochemical analysis was performed against IL-1α, IL-1β, IL-1R1 and IL-1RA; staining was evaluated using the total tissue expression of each marker obtained with an ImageJ segmentation plugin. Results: This study analyzed 44 OSCC cases, with most tumors in advanced stages (63.6%) and a five-year overall survival (OS) rate of 54.4%. Immunohistochemical analysis showed significant overexpression of IL-1α, IL-1β, IL-1R1, and IL-1RA in OSCC compared to NDAE (p<0.0001). High IL-1RA expression was associated with tumor recurrence (p=0.030) and poorer OS (p = 0.018) and disease-specific survival (DSS) (p=0.028). Multivariate analysis identified IL-1RA overexpression (p=0.007) and lymph node metastasis (p=0.002) as independent risk factors for poor OS. Conclusion: High IL-1RA expression is associated with features of OSCC progression and adverse clinical outcomes. Further studies are needed to elucidate the mechanistic roles of IL-1RA and other IL-1 family members in OSCC.