Previous studies evaluating the association between weight fluctuation and mortality are limited and have conflicting results. This study will further evaluate the association between weight fluctuation and mortality in a nationally representative cohort by performing survival analysis of NHANES I and NHANES I Epidemiologic Follow-up Study (n = 8479; weighted sample = 68,200,905). This cohort was followed from 1971 to 1992 and categorized using weight change over five time points into stable non-obese, stable obese, weight gain, weight loss and weight fluctuation groups. All-cause mortality (ACM) and cardiovascular mortality (CM) were evaluated. Respondents with weight fluctuation had higher ACM (HR: 1.83, 95% CI: 1.25-2.69) and CM hazards ratios (HR: 1.86, 95% CI: 1.10-3.15) than the stable non-obese group, even after controlling for pre-existing disease, initial BMI and excluding those in poor health or incapacitated. Increased mortality was also seen in the weight loss group (ACM HR: 3.36, 95% CI: 2.47-4.55), (CM HR 4.22, 95% CI: 2.60-6.84). The stable obese group did not have increased ACM, but did have increased CM prior to the exclusion of those in poor health or incapacitated. (HR: 2.17, 95% CI: 1.10-4.28). Weight fluctuation is associated with a higher risk of all-cause and cardiovascular disease mortality in the US population, even after adjustment for pre-existing disease, initial BMI and the exclusion of those in poor health or incapacitated. Thus, health care providers should promote a commitment to maintaining weight loss to avoid weight fluctuation and consider patients' weight histories when assessing their risk status.