Objective The purpose of this study was to investigate the presence of chronic diseases in patients with oral leukoplakia (OL) compared to controls matched for age group, gender, smoking and alcohol use. Subjects and Methods This case–control study examined the general demographics, medical and social histories of 105 OL cases and 391 controls matched for age group, gender, tobacco and alcohol use. All OL cases were diagnosed based on both clinical and histopathological findings. Results Chronic diseases were significantly associated with OL, namely dyslipidaemia (p < .0001), musculoskeletal diseases (p = .0101) and asthma (p = .0052). The use of ACE inhibitors (p = .0177), opioid analgesics (p = .0300), anticoagulants (p = .0055) and statins (p = .0010) was significantly associated with OL. Dyslipidaemia (p < .0001; odds ratio [95% CI]: 6.4 [3.5–11.6]) and asthma (p = .0110; odds ratio [95% CI]: 2.2 [1.2–4.0]) were identified as independent predictors of OL in multivariate analysis, both of which were significantly more common amongst cases than controls. Conclusions Results from this first Australian study suggest that dyslipidaemia and asthma may constitute independent predictors for the presence of OL. However, longitudinal studies are needed to ascertain the temporal relationship between OL and chronic disease comorbidity and the mechanisms underlying these associations.