Aims: To test the role of fatigue and its subtypes (general, physical, emotional, mental, and vigor) in mediating the relationship between psychological distress and pain interference. Methods: Retrospective, de-identified records were examined for 431 patients seeking treatment for persistent orofacial pain. Primary diagnoses of participants were muscle pain (29.8%), joint pain (26.0%), neuropathic pain (19.5%), and other (ie, fibromyalgia, centrally mediated myalgia, tendonitis, dental pain, cervical spine displacement, and no diagnosis; 24.7%). Mediation models were tested with distress as the independent variable, interference as the dependent variable, and fatigue or its subtypes as the mediators. Results: After controlling for pain duration and average levels of pain, total fatigue mediated the relationship between distress and interference. Fatigue subtypes partially mediated the relationship between distress and interference, but mediation was strongest with the composite fatigue variable. The results, however, should be interpreted cautiously, as data were collected at a single time point and do not imply causality. Conclusion: These results suggest that interventions targeted specifically at fatigue symptoms may be helpful for reducing interference and improving quality of life in patients with persistent orofacial pain. Keywords: fatigue, orofacial pain, pain interference, psychological distress