To date, little is known about the risk factors for the development of chronic myeloid leukemia (CML). Obesity, measured as body mass index, has been identified as a possible risk factor for several solid tumors as well as some adult hematopoietic malignancies. This case-control study (N = 253 cases and 270 controls), conducted at the University of Texas M. D. Anderson Cancer Center, investigated the role of obesity and adulthood weight gain in CML risk. Cases and controls were similar with respect to smoking, alcohol consumption, and occupational solvent and ionizing radiation exposure. Cases were significantly more likely to have a history of occupational exposure to agricultural chemicals (11% cases versus 3% controls, P = 0.001). Cases were more likely to be obese during adulthood compared with controls at age 25 [odds ratios (OR) = 4.29; 95% confidence intervals (95% CI), 1.63-11.3], at age 40 (OR = 5.12; 95% CI, 1.92-13.6), and at diagnosis (OR = 3.09; 95% CI, 1.56-6.13). Obesity at all ages was found to be an independent risk factor, with a significant dose-response effect. Among participants > or =45 years, cases gained significantly more weight each year between ages 25 and 40 compared with controls (0.78 versus 0.44 kg/y, P < 0.001) with the association strongest among those who gained >1 kg/y between 25 and 40 years of age (OR, 3.63; 95% CI, 1.46-9.04). Our results suggest that obesity and adulthood weight gain play important roles in CML risk. Several plausible biological mechanisms have been proposed and warrant further investigation. In the future, cancer prevention interventions aimed at reducing the incidence of CML could be developed.