BACKGROUND: The incidence of oral cavity squamous cell carcinoma (OCSCC) is increasing among non-smokers. This study investigates the association between local and systemic oral health determinants and OCSCC in never-smoking adults. METHODS: A case-control study using the National Institutes of Health All of Us database was conducted. Lifetime exposures to periodontal disease, acquired absence of teeth, hyperlipidemia, hyperglycemia, HIV, oral-related autoimmune diseases, depression, and eating disorders were analyzed. Multivariate logistic regression estimated odds ratios (ORs) and 95% confidence intervals to identify independent OCSCC risk factors. RESULTS: Several risk factors were independently associated with OCSCC: periodontal disease (OR 4.99), hyperlipidemia (OR 1.53), HIV infection (OR 2.96), oral-related autoimmune diseases (OR 2.40), depression (OR 1.51), and eating disorders (OR 8.46). Acquired absence of teeth and hyperglycemia did not show statistical significance. CONCLUSIONS: This study highlights the complex pathophysiology of OCSCC in never-smoking adults and underscores the need for comprehensive risk assessment and prevention strategies.