OBJECTIVE: To investigate whether cardiovascular risk factors can explain the higher carotid intima-media thickness (CIMT) in Indigenous compared with European Australians. DESIGN: Cross-sectional study in three subgroups. PATIENTS: Non-diabetic urban European (n = 86), urban Indigenous (n = 69), and remote Indigenous (n = 60) Australians aged 25-64 years. MEASUREMENTS: CIMT, age, sex, anthropometry, blood pressure, smoking status, fasting glucose and insulin, haemoglobin (Hb)A1c, homocysteine, C-reactive protein (CRP), lipids, urinary albumin and creatinine. RESULTS: CIMT and levels of risk factors, except fasting glucose and total cholesterol, worsened across the three groups. Log(n) fasting insulin [beta = 0.022, 95% confidence interval (CI) 0-0.0439], age (beta = 0.006, 95% CI 0.004-0.007), gender (female beta = -0.005 vs. male, 95% CI -0.084 to -0.026), mean arterial pressure (MAP) (beta = 0.001, 95% CI 0.001-0.002) and ethnicity/location [urban Indigenous (beta = 0.027, 95% CI -0.010 to 0.064 vs. European); remote Indigenous (beta = 0.083, 95% CI 0.042-0.123 vs. European)] explained 41% of variance in CIMT. Significant interactions were seen for ethnicity/location with age (P = 0.014) and MAP (P = 0.018). Age was consistently associated with CIMT across the three populations, and was associated with larger increments in CIMT for the Indigenous subgroups (beta = 0.007, 95% CI 0.005-0.009 urban; beta = 0.007, 95% CI 0.004-0.010 remote) compared with Europeans (beta = 0.003, 95% CI 0.002-0.006) in models including age, sex and MAP. MAP was only associated with CIMT in the remote Indigenous subgroup. CONCLUSION: After adjusting for selected risk factors, CIMT in remote Indigenous participants was still higher than in Europeans. The slope of the association between age and CIMT steepened from urban Europeans to remote Indigenous.