Background Strong evidence shows that physical inactivity increases the risk of many adverse health conditions, including major non-communicable diseases such as coronary heart disease, type 2 diabetes, and breast and colon cancers, and shortens life expectancy. Because much of the world's population is inactive, this link presents a major public health issue. We aimed to quantify the effect of physical inactivity on these major non-communicable diseases by estimating how much disease could be averted if inactive people were to become active and to estimate gain in life expectancy at the population level. Methods For our analysis of burden of disease, we calculated population attributable fractions (PAFs) associated with physical inactivity using conservative assumptions for each of the major non-communicable diseases, by country, to estimate how much disease could be averted if physical inactivity were eliminated. We used life-table analysis to estimate gains in life expectancy of the population. Findings Worldwide, we estimate that physical inactivity causes 6% (ranging from 3.2% in southeast Asia to 7.8% in the eastern Mediterranean region) of the burden of disease from coronary heart disease, 7% (3.9-9.6) of type 2 diabetes, 10% (5.6-14.1) of breast cancer, and 10% (5.7-13.8) of colon cancer. Inactivity causes 9% (range 5.1-12.5) of premature mortality, or more than 5.3 million of the 57 million deaths that occurred worldwide in 2008. If inactivity were not eliminated, but decreased instead by 10% or 25%, more than 533 000 and more than 1.3 million deaths, respectively, could be averted every year. We estimated that elimination of physical inactivity would increase the life expectancy of the world's population by 0.68 (range 0.41-0.95) years. Interpretation Physical inactivity has a major health effect worldwide. Decrease in or removal of this unhealthy behaviour could improve health substantially. Funding None.