Background Microvascular disease (MVD) is a potential contributor to the pathogenesis of diabetes mellitus-related cardiac dysfunction. However, there is a paucity of data on the link between MVD and incident heart failure (HF) in type 2 diabetes mellitus. We examined the association of MVD with incident HF in adults with type 2 diabetes mellitus. Methods and Results A total of 4095 participants with type 2 diabetes mellitus and free of HF were assessed for diabetes mellitus-related MVD including nephropathy, retinopathy, or neuropathy at baseline in the Look AHEAD (Action for Health in Diabetes) study. Incident HF events were prospectively assessed and adjudicated using hospital and death records. Cox models were used to generate hazard ratios and 95% CIs for HF. Of 4095 participants, 34.8% (n=1424) had MVD, defined as the presence of ≥1 of nephropathy, retinopathy, or neuropathy at baseline. Over a median of 9.7 years, there were 117 HF events. After adjusting for relevant confounders, participants with MVD had a 2.5-fold higher risk of incident HF than those without MVD (hazard ratio, 2.54; 95% CI, 1.73-3.75). This association remained significant after additional adjustment for interval development of coronary artery disease (hazard ratio, 2.42; 95% CI, 1.64-3.57). The hazard ratios for HF by type of MVD were 2.22 (95% CI, 1.51-3.27), 1.30 (95% CI, 0.72-2.36), and 1.33 (95% CI, 0.86-2.07) for nephropathy, retinopathy, and neuropathy, respectively. CONCLUSIONS MVD is associated with an excess HF risk in individuals with type 2 diabetes mellitus after adjusting for other known risk factors. Our findings underscore the contribution of MVD to the development of diabetes mellitus-related HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.