OBJECTIVE: Indigenous Australians have rates of cardiovascular (CVD) mortality some seven to 10-fold higher than non-Indigenous Australians aged 25-64 years. We aimed to evaluate the impact of type 2 diabetes and components of the metabolic syndrome on carotid intima-media thickness (CIMT) as a marker of cardiovascular risk in Indigenous Australians living in remote and urban environments and in Australians of European ancestry. DESIGN, PATIENTS AND MEASUREMENTS: CIMT was measured by high-resolution B-mode ultrasound imaging of the common carotid artery in 119 remote Indigenous, 144 urban Indigenous and 122 urban European Australians with and without diabetes. RESULTS: In nondiabetic participants, CIMT was lowest in Europeans (mean (SD) 0.64 mm (0.10)), higher in urban Indigenous Australians (0.67 mm (0.12)) and highest in remote Indigenous Australians (0.73 mm (0.15), P < 0.001). CIMT was higher with diabetes with the same pattern observed between populations: 0.73 mm, 0.79 mm and 0.82 mm, respectively (P < 0.001). Traditional risk factors (age, male gender, blood pressure and HbA1c) explained 35-45% of the variance of CIMT within each population group. However, differences in CIMT between population groups were maintained after adjustment for these cardiovascular risks plus cholesterol and smoking (P < 0.001). Factor analysis revealed that variables of the metabolic syndrome, together with smoking and elevated C-reactive protein (CRP) and urinary albumin-creatinine ratio (ACR), are likely to explain the higher CIMT in Indigenous Australians (and the urban-remote gradient). Unmeasured variables (genetic, psychosocial and socioeconomic) may also contribute to higher CIMT in these populations. CONCLUSION: Glycaemic control and metabolic syndrome components contribute significantly to premature atherogenesis in Indigenous Australians and we recommend that therapy should be targeted accordingly.