Although obesity is a risk factor for mortality, evidence that weight loss improves survival is limited. The relation between self-reported previous maximum weight, weight loss, and subsequent mortality was examined in 2,140 men and 2,550 women aged 45-74 years who participated in the First National Health and Nutrition Examination Survey (1971-1975) and survived the next 5 years. Vital status was determined through 1987. Among men and women whose maximum body mass index (weight (kg)/height (m)2) was between 26 and 29, risk of death increased with increasing weight loss, after adjustment for age, race, smoking, parity, preexisting illnesses, and maximum body mass index. Subjects who lost 15% or more of their maximum weight had over twice the mortality risk of those who lost less than 5%. At maximum body mass indices of 29 or higher, mortality risk increased with the amount of weight lost in women, but weight loss of 5% to < 15% appeared to lessen mortality risk in men. Generalization from these results is limited by the older age range of the sample and the inability to adequately distinguish voluntary from involuntary weight loss in this study. However, these findings suggest that prevention of severe overweight may be more generally effective than weight loss in reducing obesity-related mortality in the US population.