Weight cycling has been associated with an increased risk of death in some studies, but few studies differentiated weight cycling initiated by intentional weight loss from that initiated by illness. The association of weight cycling with death was examined among 55,983 men and 66,655 women in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2008. A weight cycle was defined as an intentional loss of 10 or more pounds (≥4.5 kg) followed by regain of that weight, and the lifetime number of weight cycles was reported on a questionnaire administered at enrollment in 1992. A total of 15,138 men and 10,087 women died during follow-up, which ended in 2008. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression models. When the models were adjusted for age only, weight cycling was positively associated with mortality (P for trend < 0.0001). However, after adjustment for body mass index and other risk factors, low numbers of weight cycles (1-4 cycles) were associated with slightly lower mortality rates (hazard ratio (HR) = 0.93, 95% confidence interval (CI): 0.89, 0.97 in men and HR = 0.93, 95% CI: 0.89, 0.98 in women), whereas high numbers of weight cycles (≥20 cycles) were not associated with mortality (HR = 1.03, 95% CI: 0.89, 1.19 in men and HR = 0.99, 95% CI: 0.88, 1.12 in women). These results do not support an increased risk of mortality associated with weight cycling.