Little is known about the interactions between hyperhomocysteinemia and metabolic syndrome (MetS) in individuals at risk for atherosclerosis. The aim of this study was to assess the burden of atherosclerosis in patients with MetS and hyperhomocysteinemia. We assessed the interaction of MetS with other risk factors including hyperhomocysteinemia in 972 patients with a history of stroke, transient ischemic attack, or carotid stenosis. MetS was defined as by the International Diabetes Federation as body mass index ≥30 kg/m² and two or more of the following: hypertension, high triacylglycerides, and low high-density lipoprotein. We defined hyperhomocysteinemia as plasma total homocysteine ≥14 µmol/L. Patients with diabetes were excluded. Carotid total plaque area (TPA), a strong predictor of cardiovascular risk, was measured by carotid ultrasound. The association of TPA with MetS, and interaction with related risk factors, was assessed by multiple linear regression. Complete data were available on 972 non-diabetic patients. Of these, 179 (18.4%) had MetS. Patients with MetS and hyperhomocysteinemia (P < 0.001) or smoking (P=0.02) had a higher TPA compared with those with MetS and normal plasma total homocysteine levels. In linear regression, there was a significant association of MetS (P=0.004), hyperhomocysteinemia (P=0.01), and smoking (P=0.004) with increased TPA. Patients with MetS and smoking or hyperhomocysteinemia are at particularly high cardiovascular risk. Targeted atherosclerosis prevention should include identification and treatment of MetS, smoking, and hyperhomocysteinemia (including that due to unrecognized metabolic vitamin B12 deficiency).