To examine the role of heme oxygenase (HO)‐1 in the pathophysiology of vascular diseases, we generated mice deficient in both HO‐1 and apolipoprotein E (HO‐1^−/−apoE^−/−). Despite similar total plasma cholesterol levels in response to hypercholesterolemia, HO‐1^−/−apoE^−/− mice, in comparison with HO‐1^+/+apoE^−/− mice, had an accelerated and more advanced atherosclerotic lesion formation. In addition to greater lipid accumulation, these advanced lesions from HO‐1^−/−apoE^−/− mice contained macrophages and smooth muscle α‐actin‐positive cells. We further tested the role of HO‐1 on neointimal formation in a mouse model of vein graft stenosis. Autologous vein grafts in HO‐1^−/− mice showed robust neointima consisting of α‐actin‐positive vascular smooth muscle cells (VSMC) 10 days after surgery in comparison to the smaller neointima formed in autologous vein grafts in HO‐1^+/+ mice. However, at 14 days after surgery, the neointima from composite vessels of HO‐1^−/− mice was composed mainly of acellular material, indicative of substantial VSMC death. VSMC isolated from HO‐1^−/− mice were susceptible to oxidant stress, leading to cell death. Our data demonstrate that HO‐1 plays an essential protective role in the pathophysiology of atherosclerosis and vein graft stenosis.