In order to determine whether weight loss explains high mortality rates in those with a low body mass index (BMI), the relationships between BMI, rate of weight gain and mortality were examined in Pima Indians. Subjects were 814 diabetic and 1814 nondiabetic participants in a longitudinal survey who had at least two examinations after age 20. Median duration of follow-up was 8.1 (range 0.03-25.1) years. BMI showed a U-shaped relationship with mortality rates in men with the lowest rates in the 30-35 kg/m2 category; an inverse relationship was seen in women. Subjects who were losing weight had higher mortality rates than those who were gaining. However, excess mortality among the lightest subjects was present among those who were gaining weight. Among nondiabetic subjects, the mortality ratio (MR) for BMI < 25 kg/m2 compared with 30-35 kg/m2 was 1.5 [95% confidence interval (CI) 1.0-2.2] unadjusted for weight gain, while the adjusted MR was 1.3 [95% CI 0.9-1.9]. Weight loss, which may reflect underlying illness, is associated with high mortality rates in Pima Indians but does not fully account for the high mortality in the lightest individuals.