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OBJECTIVE: Hyperhomocysteinemia (HHcy) is a potent risk factor for diabetic cardiovascular diseases (CVD). We have previously reported that HHcy potentiates type 1 diabetes-induced inflammatory monocyte (MC) differentiation, vascular dysfunction, and atherosclerosis. However, the effects of HHcy on vascular inflammation in type 2 diabetes mellitus (T2DM) and the underlying mechanism are unknown. APPROACH AND RESULTS: Here, we demonstrate that HHcy was induced by a high methionine diet in control mice (homocysteine (Hcy) 129 μM), which was further worsened in T2DM db/db mice (Hcy 180 μM) with aggravated insulin intolerance. HHcy potentiated T2DM-induced mononuclear cell (MNC), MC, inflammatory MC (CD11b(+)Ly6C(+)), and M1 macrophage differentiation in periphery and aorta, which were rescued by folic acid-based Hcy-lowering therapy. Moreover, HHcy exacerbated T2DM-impaired endothelial-dependent aortic relaxation to acetylcholine. Finally, Transfusion of bone marrow cells depleted for Ly6C by lentivirus-Ly6C shRNA transduction improved insulin intolerance and endothelial-dependent aortic relaxation in HHcy+T2DM mice. CONCLUSIONS: HHcy potentiated systemic and vessel wall inflammation, and vascular dysfunction partially via inflammatory MC subset induction in T2DM. Inflammatory MC may be a novel therapeutic target for insulin resistance, inflammation, and cardiovascular complications in HHcy+T2DM.