Simple SummaryImmunosuppression is a medical condition in which a person’s immune system is unable to function properly, or it does not function at all. It is a well-known fact that an ill-functioning immune system can favor the generation and development of potentially malignant lesions, autoimmune and allergic diseases, and even neoplasms. At present, the amount of risk for the development of oral cancer in immunosuppressed patients has not been quantitatively reported. Such a topic has been investigated, revealing that immunosuppression increases the risk of developing cancer from 0.2% to 1% (95% CI: 0.2% to 1.4%), giving further importance to the accurate follow-up of this category of patients.AbstractEven if the relationship between immunosuppression and increased incidence of systemic cancers is well known, there is less awareness about the risk of developing oral cancer in immunosuppressed patients. The aim of this review was to evaluate the association between immunosuppression and the development of oral cancer. Two authors independently and, in duplicate, conducted a systematic literature review of international journals and electronic databases (MEDLINE via OVID, Scopus, and Web of Science) from their inception to 28 April 2023. The assessment of risk of bias and overall quality of evidence was performed using the Newcastle–Ottawa Scale and GRADE system. A total of 2843 articles was identified, of which 44 met the inclusion criteria and were included in either the qualitative or quantitative analysis. The methodological quality of the included studies was generally high or moderate. The quantitative analysis of the studies revealed that immunosuppression should be considered a risk factor for the development of oral cancer, with a percentage of increased risk ranging from 0.2% to 1% (95% CI: 0.2% to 1.4%). In conclusion, the results suggest that a constant and accurate follow-up should be reserved for all immunosuppressed patients as a crucial strategy to intercept lesions that have an increased potential to evolve into oral cancer.