Abstract Background Although South Asians are the largest ethnic minority group in the UK, and the largest ethnic group worldwide, few studies have investigated patterns of mortality in South Asians. Methods We investigated 16,391 South Asian and 6,970 European men and women living in the UK, and participating in the London Life Sciences Prospective Population study. Participants were recruited in 2002-2008, and survival determined to 2019. We examined relationships of clinical, anthropometric, and lifestyle risk factors to mortality outcomes. Findings: Compared to Europeans, South Asians had higher prevalence of diabetes, cardiovascular disease, and hypertension, higher waist-hip ratio, fasting glucose, insulin and triglycerides, but lower smoking rates and HDL cholesterol (all P<0.001). Age and sex adjusted all-cause mortality was lower (Hazard Ratio (HR): 0.75 [0.68-0.81], P<0.001), all-cancer mortality was lower (HR 0.50 [0.43-0.58], P<0.001), and coronary heart disease (CHD) mortality was higher (HR 1.29 [1.05-1.60], P<0.01) in South Asians compared to Europeans. Mortality rates were ~50% lower for 9 of the 10 most common cancers in South Asians. After adjusting for risk factors, ethnic differences were attenuated only for CHD mortality. Interpretation: All-cause and cancer mortality are lower, but CHD mortality is higher, in South Asians compared to Europeans. Measured risk factors do not explain lower all-cause and all-cancer mortality, but do account for higher CHD mortality. Our findings provide evidence for population-specific exposures protective against cancers in South Asians, as well as the motivation to further improve cardiovascular risk reduction in this major ethnic group.