Few studies have evaluated the combined impact of following recommended lifestyle behaviors on cancer, cardiovascular disease (CVD) and all-cause mortality, and most included tobacco avoidance. Because 80% of Americans are never or former smokers, it is important to consider the impact of other recommended behaviors. In 1992 and 1993, 111,966 nonsmoking men and women in the Cancer Prevention Study-II Nutrition Cohort completed diet and lifestyle questionnaires. A score ranging from 0 to 8 points was computed to reflect adherence to the American Cancer Society cancer prevention guidelines on body mass index, physical activity, diet, and alcohol consumption, with 8 points representing optimal adherence. Multivariable-adjusted relative risks (RR) of death and 95% CI were computed by Cox proportional hazard regression. During 14 years of follow-up, 10,369 men and 6,613 women died. The RR of all-cause mortality was lower for participants with high (7, 8) versus low (0-2) scores (men, RR = 0.58, 95% CI: 0.53-0.62; women, RR = 0.58, 95% CI: 0.52-0.64). Inverse associations were found with CVD mortality (men, RR = 0.52, 95% CI: 0.45-0.59; women, RR = 0.42, 95% CI: 0.35-0.51) and cancer mortality (men, RR = 0.70, 95% CI: 0.61-0.80; women, RR = 0.76, 95% CI: 0.65-0.89). Similar associations, albeit not all statistically significant, were observed for never and former smokers. Adherence to cancer prevention guidelines for obesity, diet, physical activity, and alcohol consumption is associated with lower risk of death from cancer, CVD, and all causes in nonsmokers. Beyond tobacco avoidance, following other cancer prevention guidelines may substantially lower risk of premature mortality in older adults. ©2011 AACR.