The COVID-19 pandemic is perhaps one of the most important events of the 21st century. Periodontitis is one of the most prevalent diseases of the oral cavity. Due to possible pathways of interaction between these two diseases, we investigated their association. The study population consisted of hospitalized patients with established COVID-19 diagnoses. Patients with mild to moderate COVID-19 were considered controls, while cases had severe to critical COVID-19. Periodontal examination and serum and saliva sampling were performed for each patient. Relevant medical data were extracted from patients' hospital files. Of the enrolled patients, 122 were included in the statistical analyses. The severity of periodontitis was directly and significantly correlated with the severity of COVID-19 (P < 0.001). Patients with generalized stage III or IV periodontitis displayed an adjusted odds ratio of 4.24 for severe to critical COVID-19. Salivary and serum interleukin-6 levels were significantly associated with COVID-19 severity (P values: 0.002 and 0.004, respectively). Hospitalization length was significantly associated with the severity of periodontitis (P = 0.004). Clinical attachment level and gingival index were associated with increased odds for adverse events (P values: 0.004 and 0.035, respectively), while number of remaining teeth was associated with decreased odds for adverse events (P = 0.023). This study showed that the severity of periodontitis is associated with the severity of COVID-19. This association might manifest as increased odds of adverse events. COVID-19 severity was associated with higher levels of salivary and serum interleukin-6 levels.