The etiology of myelodysplastic syndromes (MDS) is not well understood. The authors examined the relations of obesity and lifestyle factors to MDS in a cohort of 471,799 persons aged 50–71 years who were recruited into the National Institutes of Health-AARP Diet and Health Study, a large US prospective study, in 1995–1996. Incident MDS was diagnosed in 193 persons during 2001–2003. A significant positive association was observed between body mass index (BMI; weight (kg)/height (m)2) at baseline and MDS. Compared with persons with a BMI less than 25.0, the hazard ratios for persons with BMIs of 25.0–<30.0 and ≥30.0 were 1.15 (95% confidence interval (CI): 0.81, 1.64) and 2.18 (95% CI: 1.51, 3.17; P for trend < 0.001), respectively. The association was not affected by physical activity, cigarette smoking, or alcohol intake. As reported in previous studies, the risk of MDS was elevated among former smokers (hazard ratio=1.68, 95% CI: 1.17, 2.41) and current smokers (hazard ratio=3.17, 95% CI: 2.02, 4.98) as compared with never smokers. Physical activity, alcohol consumption, meat intake, and fruit and vegetable intake did not appear to significantly influence the risk of MDS in this analysis. This prospective investigation of MDS implicates both obesity and smoking as modifiable risk factors.