Asian Indians appear particularly susceptible to coronary heart disease compared with other ethnic groups. We compared the effects of vascular risk factors on carotid intima-media thickness (IMT) in a population of South Asians from Andhra Pradesh, India with a population of Caucasians from Perth, Australia. Cardiovascular risk factors and ultrasound-assessed carotid IMT were measured in randomly selected adults from two villages in rural India (n=303) and compared to those for randomly sampled adults from Australia (n=1111). Regression models with interaction terms were used to compare the strengths of associations between risk factors and carotid IMT, in these two populations. There were stronger associations of cholesterol (p for interaction=0.009) and diabetes (p=0.04) with carotid IMT in the Indian compared to the Australian population. Also, while increasing HDL-cholesterol was associated with decreasing carotid IMT in the Australian population the reverse was true for the Indian population (p<0.001). The associations with IMT of blood pressure, triglycerides, age, HDL to total cholesterol ratio, glucose, BMI, waist, waist to hip ratio and smoking were not different between the populations. Greater adverse effects of total cholesterol and diabetes on atherosclerosis and no protective effect of HDL-cholesterol amongst Asian Indians provide a novel possible explanation for observed excess rates of cardiovascular disease amongst these populations.