Insulin resistance, insulin secretion, and glucose tolerance may predict weight change. A total of 1,194 adults aged 39-69 years at baseline (46% with normal glucose tolerance according to World Health Organization criteria, 23% with impaired glucose tolerance, and 31% with type 2 diabetes mellitus who were not taking insulin) were evaluated at baseline (1992-1994) and after 5 years. Baseline insulin sensitivity (S(I)) was measured by means of a 12-sample, insulin-enhanced, frequently sampled intravenous glucose tolerance test. Insulin secretion was assessed in terms of acute insulin response and disposition index, both obtained from the frequently sampled intravenous glucose tolerance test. At follow-up, 25% of subjects had lost more than 2.27 kg (>5 pounds), 38% weighed within 2.27 kg of their baseline weight, and 37% had gained more than 2.27 kg. In separate models, greater weight loss occurred among those with type 2 diabetes than among those with either impaired glucose tolerance or normal glucose tolerance (p < 0.001); baseline acute insulin response and disposition index were positively associated and baseline fasting insulin level was inversely associated with 5-year weight change (p < 0.05 for each; data were adjusted for baseline body mass index and demographic and behavior change variables). Upon simultaneous inclusion of metabolic variables within glucose tolerance status groups, none was a significant predictor of weight loss. Apart from glucose tolerance status itself, measures of insulin metabolism appear to have little effect on weight change over 5 years.