||BACKGROUND: Several health agencies have issued guidelines promoting behaviors to reduce chronic disease risk; however, little is known about the impact of such guidelines, particularly on cancer incidence. OBJECTIVE: The objective was to determine whether greater adherence to the American Cancer Society (ACS) cancer prevention guidelines is associated with a reduction in cancer incidence, cancer mortality, and total mortality. DESIGN: The NIH-AARP Diet and Health Study, a prospective cohort study of 566,401 adults aged 50-71 y at recruitment in 1995-1996, was followed for a median of 10.5 y for cancer incidence, 12.6 y for cancer mortality, and 13.6 y for total mortality. Participants who reported a history of cancer or who had missing data were excluded, yielding 476,396 subjects for analysis. We constructed a 5-level score measuring adherence to ACS guidelines, which included baseline body mass index, physical activity, alcohol intake, and several aspects of diet. Cox proportional hazards models were used to compute HRs and 95% CIs for the association of the adherence score with cancer incidence, cancer mortality, and total mortality. All analyses included fine adjustment for cigarette smoking. RESULTS: Among 476,396 participants, 73,784 incident first cancers, 16,193 cancer deaths, and 81,433 deaths from all causes were identified in the cohort. Adherence to ACS guidelines was associated with reduced risk of all cancers combined: HRs (95% CIs) for the highest compared with the lowest level of adherence were 0.90 (0.87, 0.93) in men and 0.81 (0.77, 0.84) in women. Fourteen of 25 specific cancer sites showed a reduction in risk associated with increased adherence. Adherence was also associated with reduced cancer mortality [HRs (95% CIs) were 0.75 (0.70, 0.80) in men and 0.76 (0.70, 0.83) in women] and reduced all-cause mortality [HRs (95% CIs) were 0.74 (0.72, 0.76) in men and 0.67 (0.65, 0.70) in women]. CONCLUSIONS: In both men and women, adherence to the ACS guidelines was associated with reductions in all-cancer incidence and the incidence of cancer at specific sites, as well as with reductions in cancer mortality and total mortality. These data suggest that, after accounting for cigarette smoking, adherence to a set of healthy behaviors may have considerable health benefits. This trial was registered at www.clinicaltrials.gov as NCT00340015.