Reliable and comparable analysis of risks to health is key for preventing disease and injury. Causal attribution of morbidity and mortality to risk factors has traditionally been in the context of individual risk factors, often in a limited number of settings, restricting comparability. Our aim was to estimate the contributions of selected major risk factors to global and regional burden of disease in a unified framework. For 26 selected risk factors, expert working groups undertook a comprehensive review of published work and other sources--eg, government reports and international databases--to obtain data on the prevalence of risk factor exposure and hazard size for 14 epidemiological regions of the world. Population attributable fractions were estimated by applying the potential impact fraction relation, and applied to the mortality and burden of disease estimates from the global burden of disease (GBD) database. Childhood and maternal underweight (138 million disability adjusted life years [DALY], 9.5%), unsafe sex (92 million DALY, 6.3%), high blood pressure (64 million DALY, 4.4%), tobacco (59 million DALY, 4.1%), and alcohol (58 million DALY, 4.0%) were the leading causes of global burden of disease. In the poorest regions of the world, childhood and maternal underweight, unsafe sex, unsafe water, sanitation, and hygiene, indoor smoke from solid fuels, and various micronutrient deficiencies were major contributors to loss of healthy life. In both developing and developed regions, alcohol, tobacco, high blood pressure, and high cholesterol were major causes of disease burden. Substantial proportions of global disease burden are attributable to these major risks, to an extent greater than previously estimated. Developing countries suffer most or all of the burden due to many of the leading risks. Strategies that target these known risks can provide substantial and underestimated public-health gains.