CONTEXT Mutations in mitochondrial DNA are rare etiologies of adult-onset diabetes mellitus (DM) that merit identification to 1) prevent iatrogenic lactic acidosis, 2) prompt appropriate screening of affected patients and their families, 3) provide genetic counseling, and 4) provide an opportunity to investigate strategies for preventing diabetes. OBJECTIVE The objective of this study is to raise awareness of this rare form of adult-onset nonobese DM so that these patients are identified and provided with appropriate care. PATIENTS We describe a kindred in which four of seven siblings have adult-onset DM and sensorineural hearing loss with a confirmed genetic mutation at position 3243 in the tRNA. Two other siblings in this kindred demonstrate different phenotypes of mitochondrial disease. INTERVENTION The proband was treated with coenzyme Q10 for 1 yr. OUTCOME MEASURES Outcome measures included stress thallium exercise testing and audiometry testing. RESULTS After 1 yr of treatment of with coenzyme Q10, repeat stress thallium testing demonstrated improvement in the exercise tolerance of the proband from 7-12 min. Audiometry testing did not demonstrate a change in the rate of hearing decline. CONCLUSION Maternally inherited diabetes and deafness is a rare cause of DM that is important to diagnose because of the unique management issues and associated comorbidities. This work highlights clues to the identification of this rare monogenic form of adult- onset diabetes.