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The main objective of this study was to evaluate the effect of metformin, statins and anti-inflammatory drugs (NSAIDs) on head and neck cancer (HNC). Specifically, the potential beneficial effects on risk, survival and recurrence based on epidemiological studies. PRISMA guidelines were followed. After searching MEDLINE (PubMed), IBECS, LILACS and the Cochrane Central Register for Controlled Trials, 13 studies met the inclusion criteria and so underwent qualitative synthesis (six studies for metformin and seven for NSAIDs). No studies were found for statins. Studies varied in their methodological quality. Meta-analyses showed that metformin exerts significant beneficial effects on HNC risk (RR = 0.71 95% CI 0.61-0.84) and overall survival (RR = 1.71 95% CI 1.20-2.42). Qualitative synthesis also suggests an apparently dose-response relationship and increased benefit when administered alone. The pooled-analyses yielded an almost significant effect of NSAIDs on HNC risk (RR = 0.86 95% CI 0.74-1.01). No associations were found between aspirin use and the risk of HNC (RR = 0.98 95% CI 0.77-1.24) and overall survival (RR = 1.10 95% CI 0.89-1.36). Metformin appears to have beneficial effects on HNC risk and overall survival, with an apparently dose-response relationship and increased benefit when administered alone. NSAIDs also seem to have a modest beneficial effect on HNC risk. No definitive conclusions can be reached for aspirin as the evidence available was proved inconsistent. Further research by means of well designed and conducted studies are needed to determine firm clinical implications. Standardized assessment methods for HNC outcomes should be established and account for known confounding factors such as smoking and alcohol consumption., (Copyright © 2018 Elsevier Ltd. All rights reserved.)