Oral leukoplakia represents the most common oral potentially malignant disorder. While a number of risk factors have been identified, its aetiology remains incompletely understood, and prediction of disease progression, stability or regression, a significant challenge. While excision is often the recommended treatment to reduce the risk of malignancy, this is not always possible and ultimately numerous disease and patient characteristics impact on the decision to initiate treatment or recommend surveillance. At present, the coexistence and impact of chronic diseases in oral leukoplakia patients remains largely unexplored, yet has the potential to significantly impact on diagnosis, treatment decisions, treatment outcomes and prognosis. Exploration of comorbid conditions in oral leukoplakia may additionally lead to greater insight of risk factors and disease pathogenesis and potentially offer more opportunities for screening and early disease detection. The aim of this review is to stimulate discussion about the role of chronic diseases comorbidity in oral leukoplakia.