ABSTRACTObjectiveThis multicenter cohort study aimed to investigate the impact of antinuclear antibody (ANA) positivity on the malignant transformation potential of oral potentially malignant disorders (OPMDs) using the Observational Health Sciences and Informatics network tools for the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM).Materials and MethodsRetrospective cohort data from five medical centers were analyzed. Cox regression and 1:4 propensity score matching followed by aggregated meta‐analysis were used to evaluate association between ANA positivity and the risk of oral squamous cell carcinoma (OSCC). The index date was defined as the first day of diagnosis of OPMD. The target and comparator cohorts comprised patients who tested positive and negative for ANA within 180 days before or after the index date, respectively.ResultsAmong 27,984 OPMD patients, 1302 patients (4.65%) confirmed malignant transformation. Among these, 3035 patients had ANA laboratory data. After 1:4 PS matching, 523 and 1598 patients with positive and negative for ANA were analyzed. Meta‐analysis of the hazard ratios demonstrated that ANA positivity significantly increased the risk of malignant transformation compared to ANA negativity.ConclusionsANA positivity is a significant prognostic marker for predicting malignant transformation in patients with OPMD.