Objectives: Although causal associations between oral leukoplakia (OL), oral squamous cell carcinoma (OSCC) and high‐risk human papillomavirus (HR‐HPV) have been speculated upon in several reports, conclusive evidence has not been presented. This study investigates whether the number of cases of HR‐HPV in OL has increased over time and whether the prevalence of HR‐HPV‐positive OL differs in various parts of the world. Patients and Methods: A total of 432 patients with OL from Sweden, Brazil and Romania were analysed. Patients were divided into historical (1992–2002) and contemporary (2011–2017) cohorts from the respective countries. Seventeen patients with OL developed oral squamous cell carcinoma (OSCC). A real‐time PCR assay, targeting HPV sub‐types 6,11,16,18,31,33,35,39,45,52,56,58 and 59, was performed to detect HR‐HPV in patients with OL. Results: In the Swedish and Romanian cohorts, none of the investigated HPV sub‐types were detected. In the Brazilian cohorts, five patients with OL (3%) were positive for HR‐HPV, including four patients from the contemporary cohort (HPV 16, 31, 33) and one from the historical cohort (HPV 11). All the cases of OL that transformed into OSCC were HR‐HPV‐negative, as were the corresponding tumours. Conclusions: In summary, the prevalence of HR‐HPV in OL is low in all the tested countries, and the incidence has not changed over time. HR‐HPV in OL does not seem to be a driver of oncogenesis. [ABSTRACT FROM AUTHOR]