Background: Comorbidities have shown to highly influence the outcome and risk of death of head and neck cancer patients. The purpose of this study was to examine the comorbidities among oral cavity squamous cell carcinoma (OSCC) patients, and to investigate the impact of comorbidities on overall survival (OS) and recurrence free survival (RFS). Methods: Patients diagnosed with OSCC in Eastern Denmark in the period 2000–2014 and treated with curative intend were included. Patients data were linked to the Danish National Patients Register to identify comorbidities based on the Charlson Comorbidity Index (CCI) at the time of diagnosis and five years after diagnosis. Each patient was age-and sex-matched in a 1:10 ratio with an age and sex matched reference group. Results: A total of 1,183 patients and 11,830 controls were included. Overall this study found comorbidities to be more common among OSCC compared to the reference group both at the time of diagnosis and five years after. The 5-year OS among patients with a CCI score of zero, one, two, and three or above was 60%, 44%, 41%, and 40%, respectively. Similarly, the multivariate cox-regression analysis showed that patients with increasing CCI score also had an increasing risk of death compared to patients with no comorbidities. Conclusion: OSCC patients had significantly higher comorbidity burden at diagnosis and risk of developing additional comorbidities after diagnosis compared to the reference population. Survival outcomes decreased significantly with higher CCI.