Background: Aside from exposure to ionizing radiation and benzene, little is known about lifestyle risk factors for chronic myeloid leukemia (CML) in the general population. Methods:Weexamined the relation between lifestyle and dietary risk factors forCMLin 493,188 participants (294,271 males and 198,917 females) aged 50 to 71 years who completed a baseline questionnaire in the National Institutes of Health-AARP Diet and Health Study in 1995 to 1996. Over a median of 10.5 years of follow-up, 178 incident cases of CML (139 males and 39 females) were ascertained from state registries. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for exposures of interest, adjusting for potential confounding variables. Results: In multivariable analysis of all participants combined, female sex, years of education, and vigorous physical activity (HR for >3 times/week vs. <1 time/week 0.70; 95% CI, 0.49-0.99) were inversely associated with risk of CML, whereas smoking intensity (HR for smokers of-20 cigarettes per day vs. never smokers: 1.53; 95% CI, 1.03-2.27) and body mass (HR for BMI>30 vs. <25 kg/m2 1.46; 95% CI, 0.95-2.23) were associated with increased risk. A range of dietary factors was not associated with disease. Conclusions: This study adds to the sparse information about lifestyle factors, which affect the risk of CML in the general population. Impact: If these findings are confirmed, it would suggest thatCMLmaybe amenable to preventive strategies. Cancer Epidemiol Biomarkers Prev; 22(5); 848-54.