Background-The associations between overall lifestyle profile and cardiovascular disease (CVD) and death have been mainly investigated in cross-sectional studies. The full benefits of a healthy lifestyle may therefore be underestimated, and the magnitude of benefits associated with changes in lifestyle remains unclear. We quantified the association of changes in lifestyle profiles over 5 years with risk of CVD and all-cause mortality. Methods and Results-Lifestyle factors (ie, diet, physical activity, smoking, alcohol consumption) and body mass index were assessed and dichotomized as healthy/unhealthy among 5263 adults ages 26 to 66 in 1993-1997 and 5 years later (1998- 2002). Multivariable-adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were estimated to quantify associations of change in lifestyle with fatal/nonfatal CVD and all-cause mortality that occurred 8 to 15 years after 1998-2002. Independent of baseline lifestyles, each decrement in number of healthy lifestyle factors was, on average, associated with 35% higher risk of CVD (HR, 1.35; 95% CI, 1.12-1.63) and 37% higher risk of all-cause mortality (HR, 1.37; 95% CI, 1.10-1.70); no association was noted with increase in the number of healthy lifestyle factors (P>0.5). Individuals who maintained 4 to 5 healthy lifestyle factors had 2.5 times lower risk of CVD (HR, 0.43; 95% CI, 0.25-0.63) and all-cause mortality (HR, 0.40; 95% CI, 0.22- 0.73) than those who maintained only 0 to 1 healthy lifestyle factor. Conclusions-Our findings suggest that the benefits of healthy lifestyles may be easier lost than gained over a 5-year period. This underscores the need for efforts to promote maintenance of healthy lifestyles throughout the life course.