Data sources Four electronic databases were searched: Medline (OVID), Web of Science, Embase and Scopus. An initial search was carried out in May 2018, and this was updated in September 2020. There was no time restriction on the studies included, and the final data consisted of studies published from 2004-2020.Study selection The electronic database search yielded 2,764 abstracts, and following de-duplication, 1,873 articles were screened in accordance with the exclusion criteria. In total, 346 articles were selected for full-text screening by four pairs of blinded reviewers and 295 articles were included in the final study. The main objectives of this study were to investigate a suitable biomarker for early detection of oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs), and to assess the relationships between salivary biomarkers and risk factors for OSCC and OPMD. The Newcastle-Ottawa Scale was used for quality assessment. Most studies were considered to have a moderate risk of bias. The publications included fulfilled the following criteria: original research, human subjects with oral cavity cancer, OSCC or OPMD, aged 18 years or over, studies analysing biomarkers in saliva or salivary rinse, and studies published in English.Data extraction and synthesis Data extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline process. The following data parameters were included in the studies chosen for assessment: study design, first author, year of publication, country of study population, age, sample size, gender, salivary biomarkers, method used to analyse the biomarkers, relationships between risk factors and salivary biomarkers, and conclusions.Results Following evaluation of 295 articles and selection of suitable salivary biomarkers, 28 articles were chosen to further assess interleukins as potential biomarkers and 33 studies were found to report a relationship between salivary biomarkers and risk factors. From the data reported, IL1β, IL6 and IL8 were identified as being statistically significant and most suitable for early identification of OSCC and OPMDs. In smokers, there were significant differences found in certain biomarkers compared to controls. There were statistically non-significant relationships found between biomarkers and alcohol, as well as other risk factors.Conclusion The authors proposed that a proteomic salivary biomarker panel, including a combination of IL1β, IL6 and IL8, would be suitable for clinical validation for the early detection and screening of OPMDs and OSCC. They have also highlighted the presence of research gaps in the relationship between salivary biomarkers and risk factors for OPMDs and OSCC, and the need for further research to understand the role of biomarkers in disease initiation and progression.