BACKGROUND Impressive decreases in cardiovascular mortality have been achieved through risk factor reduction and clinical intervention, yet cardiovascular disease remains a leading cause of death nationally. OBJECTIVE To estimate up-to-date preventable fractions of cardiovascular mortality associated with elimination and reduction of 5 leading risk factors nationally and by state in the United States. DESIGN Cross-sectional and cohort studies. SETTING Nationally representative and state-representative samples of the U.S. population. PARTICIPANTS Adults aged 45 to 79 years. MEASUREMENTS Self-reported risk factor status in the BRFSS (Behavioral Risk Factor Surveillance System) 2009-2010 was corrected to approximate clinical definitions. The relative hazards of cardiovascular death (International Classification of Diseases, 10th Revision, codes I00 to I99) associated with risk factors were estimated using data from NHANES (National Health and Nutrition Examination Survey) (1988-1994 and 1999-2004, followed through 2006). RESULTS The preventable fraction of cardiovascular mortality associated with complete elimination of elevated cholesterol levels, diabetes, hypertension, obesity, and smoking was 54.0% for men and 49.6% for women in 2009 to 2010. When the more feasible target of reducing risk factors to the best achieved levels in the states was considered, diabetes (1.7% and 4.1%), hypertension (3.8% and 7.3%), and smoking (5.1% and 4.4%) were independently associated with the largest preventable fractions among men and women, respectively. With both targets, southern states had the largest preventable fractions, and western states had the smallest. LIMITATION Self-reported state data; mortality hazards relied on baseline risk factor status. CONCLUSION Major modifiable cardiovascular risk factors collectively accounted for half of cardiovascular deaths in U.S. adults aged 45 to 79 years in 2009 to 2010. Fewer than 10% of cardiovascular deaths nationally could be prevented if all states were to achieve risk factor levels observed in the best-performing states. PRIMARY FUNDING SOURCE Robert Wood Johnson Foundation.