Background— Data are limited regarding whether the presence of diabetes mellitus (DM) influences the benefit of cardiac resynchronization with defibrillator therapy (CRT-D) in heart failure (HF) patients. Methods and Results— The effect of CRT-D was evaluated in 1817 patients who were enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Patients were minimally symptomatic (New York Heart Association class I or II), with ejection fraction ≤0.30 and QRS ≥130 ms. We used Cox regression to determine hazard ratio (HR) of CRT-D versus implantable cardioverter-defibrillator (ICD) therapy for the risk of HF event or death, whichever came first (MADIT-CRT primary end point), in DM (n=552) and non-DM (n=1265) patients. Compared with the non-DM patients, those with DM had more coronary risk factors. During an average follow-up of 2.4 years, DM patients had significantly more primary end point events than non-DM patients (26.6% versus 18%, P <0.001). CRT-D was associated with a significant reduction in risk of primary end point in both DM (HR=0.56, P <0.001) and non-DM patients (HR=0.67, P =0.003). Compared with non-DM patients, CRT-D:ICD HRs in DM patients were lower in the total population, and in subgroups with ischemic cardiomyopathy (0.63 versus 0.64), nonischemic cardiomyopathy (0.39 versus 0.73), and left bundle-branch block (0.36 versus 0.50). There were no significant differences in ventricular remodeling, arrhythmia events, or device-related complications between DM and non-DM patients. Conclusions— Patients with diabetes, left ventricular dysfunction, mildly symptomatic HF, and wide QRS complex derive similar benefit from CRT-D compared with patients without diabetes. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00180271.