BackgroundOral cavity cancer (OCC) and oropharyngeal cancer (OPC) are two common malignancies whose mortality is worryingly increasing worldwide. However, few studies have estimated the mortality trends for these cancers in the coming years. This study analysed the mortality rates for OCC and OPC observed between 1980 and 2019 to generate a predictive model for the next 25 years in Spain.MethodsMid-year population data and death certificates for the period 1980–2019 were obtained from the Spanish National Institute of Statistics. The Nordpred program (Norwegian Cancer Registry, Oslo, Norway) was used to calculate adjusted mortality rates as well as estimated mortality projections with an age-period-cohort model for the period 2020–2044.ResultsThe specific mortality rate per 100,000 inhabitants for OCC decreased from 2.36 (1980–1984) to 2.17 (2015–2019) and is expected to decline to 1.68 (2040–2044), particularly in males. For OPC, mortality rates rose from 0.67 (1980–1984) to 1.23 (2015–2019) and are projected to drop to 0.71 (2040–2044). In the group of females > 65 years predictions showed rising mortality rates for both OCC and OPC. The predictive model projects more deaths in females than in males for OCC in the period 2040–2044, while deaths for OPC will decrease in males and gradually increase in females.ConclusionsAlthough OCC mortality rates have been found to decrease in males in the last observed decades, there is still room to improve them in females > 65 years in the future by promoting campaigns against smoking and alcohol consumption. OPC mortality will become a growing health problem. Vaccination campaigns for the prevention of human papillomavirus-associated cancers may have a long-term impact on the mortality of these cancers, which should be evaluated in upcoming studies.Clinical relevanceOur findings highlighted the importance of closely monitoring OCC and OPC mortality rates in the coming years by age group and sex, and the need to continue preventive measures against the main known risk factors, such as tobacco, alcohol, and human papillomavirus infection.