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Physical activity is associated to a lower risk of mortality from all-causes and from coronary heart disease. The long-term effects of changes in physical activity on coronary heart disease are, however, less known. We examined the association between changes in leisure time physical activity and the risk of myocardial infarction (MI), ischemic heart disease (IHD), and all-cause mortality as well as changes in blood pressure in 4,487 men and 5,956 women in the Copenhagen City Heart Study. Physical activity was measured in 1976-1978 and 1981-1983 and participants were followed in nation-wide registers until 2009. Men who decreased physical activity by at least two levels and women who decreased by one level had a higher risk of MI relatively to an unchanged physical activity level (hazard ratio [HR] = 1.74, 95% confidence interval [95% CI]: 1.17-2.60 and HR = 1.30, 95% CI: 1.03-1.65). Similar associations were found for IHD although only significant in women. In all-cause mortality, men who increased physical activity had a lower risk and both men and women who reduced physical activity had a higher risk compared to an unchanged physical activity level. No association between changes in physical activity and blood pressure was observed. Findings from this prospective study suggest that changes in physical activity affect the risk of MI, IHD and all-cause mortality. A decrease in physical activity was associated to a higher risk of coronary heart disease.