Objective.Indirect evidence suggests a role for heme oxygenase-1 (HO-1) in limiting diabetic vasculopathy. The goal of this study was to assess the role of HO-1 in the development of microvascular lesions within glomeruli during diabetes mellitus using a mouse model with specific alteration of theHmox1gene.Approach and Results.The effects ofHmox1haploinsufficiency were studied as a means of assessing the intrinsic contribution of HO-1 in the development of renal microvascular lesions during diabetes. Renal function and histology were analyzed 10 weeks after diabetes induction with streptozotocin. DiabeticHmox1^+/−mice showed higher levels of albuminuria and blood urea compared to their wild-type diabetic littermates. More severe glomerular microvascular lesions were also observed in the diabeticHmox1^+/−mice. This was associated with a renal increase in the expression of the oxidative stress marker, nitrotyrosine.Conclusions.GeneticHmox1partial deficiency is sufficient to sensitize mice to the development of diabetic glomerular microvascular lesions. HO-1 exerts antioxidant effects in the kidney during diabetes mellitus. These have protective effects on the development of glomerular endothelial injury.