Simple SummaryOral cancer has a global incidence of 377,713 new cases and 177,757 deaths annually, according to GLOBOCAN, IARC, and the WHO. Oral squamous cell carcinoma (OSCC) represents around 90% of all oral malignancies and carries a 5-year mortality rate close to 50%. Hanahan and Weinberg introduced a set of defining characteristics that all malignant neoplastic cells are believed to possess, which have had a profound impact on the scientific community. Among these hallmarks of cancer that were identified, the ability to evade growth suppressor signals is of notable relevance in oncogenesis. These actions are essentially carried out through the functions of tumor suppressor genes, the gene RB being singularly relevant, encoding the tumor suppressor retinoblastoma protein (pRb). Loss of pRb expression has a remarkable influence on tumor development, both in its initiation and in its early and late progression; nevertheless, it is striking to note that in oral carcinogenesis there are no meta-analytical studies designed in order to investigate the evidence base on this research topic. This is the first systematic review and meta-analysis, based on 20 studies and 2451 patients with OSCC, demonstrating that the loss of pRb function is a factor associated with improved survival in patients with oral cancer.AbstractThis systematic review and meta-analysis aims to evaluate the scientific evidence on the implications of retinoblastoma protein (pRb) alterations in oral cancer, in order to determine its prognostic and clinicopathological significance. PubMed, Embase, Web of Science, and Scopus were searched for studies published before February 2022, with no restrictions by publication date or language. The quality of the studies using the Quality in Prognosis Studies tool (QUIPS tool). Meta-analysis was conducted to achieve the proposed objectives, as well as heterogeneity, subgroup, meta-regression, and small study-effects analyses. Twenty studies that met the inclusion criteria (2451 patients) were systematically reviewed and meta-analyzed. Our results were significant for the association between the loss of pRb expression and a better overall survival (HR = 0.79, 95%CI = 0.64–0.98,p= 0.03), whereas no significant results were found for disease-free survival or clinico-pathological parameters (T/N status, clinical stage, histological grade). In conclusion, our evidence-based results demonstrate that loss of pRb function is a factor associated with improved survival in patients with OSCC. Research lines that should be developed in the future are highlighted.