This study aims to identify how mental illness severity interacts with oral anticoagulant (OAC) patterns among people with atrial fibrillation (AF). AF patients with comorbid mental illness (classified using ) were identified from the South London and Maudsley Biomedical Research Centre Case Register. CHADS-VASc and ORBIT scales were used to calculate stroke and bleeding risks, respectively, whereas Health of the Nation Outcome Scales (HoNOS) assessment was used for functional impairment. Overall, 2,105 AF patients were identified between 2011 and 2019. Serious mental illness (SMI) was associated with lower prescription of any OAC (adjusted risk ratio [aRR]: 0.94; 95% CI, 0.90-0.99). A total of 62% of SMI patients at risk of stroke were not prescribed an OAC. In the AF cohort, alcohol or substance dependence and activities of daily living (ADL) impairment were associated with lower prescription of warfarin (aRR: 0.92; 95% CI, 0.86-0.98 and aRR: 0.96; 95% CI, 0.93-0.99, respectively). Among people with AF and SMI, warfarin was less likely to be prescribed to people with self-injury (aRR: 0.84; 95% CI, 0.77-0.91), hallucinations or delusions (aRR: 0.92; 95% CI, 0.85-0.99), ADL impairment (aRR: 0.91; 95% CI, 0.84-0.99), or alcohol or substance dependence (aRR: 0.92; 95% CI, 0.87-0.98). Among people with AF and comorbid substance use disorder, self-injury (aRR: 0.78; 95% CI, 0.64-0.96), cognitive problems (aRR: 0.84; 95% CI, 0.70-0.99), and other mental illnesses (aRR: 0.83; 95% CI, 0.70-0.99) were associated with lower prescription of warfarin. An OAC treatment gap for AF patients with comorbid SMI relative to other mental illnesses was identified. The gap was wider in those with dependence comorbidities, positive symptoms, self-injury, or functional impairment. . © Copyright 2024 Physicians Postgraduate Press, Inc.