Several recent prospective studies have reported that obesity is associated with an increased risk for chronic kidney disease (CKD), but it is unknown whether weight gain increases the risk for CKD if one remains within the "normal" category of body mass index (BMI). We prospectively followed a cohort of 8792 healthy men who had no known risk factors for CKD and participated in a comprehensive health evaluation program at a large worksite. During 35,927 person-years of follow-up, 427 new incident cases of CKD (estimated GFR <64 ml/min per 1.73 m(2)) developed. Cox proportional hazards modeling revealed that in both the normal-weight and overweight groups, a U-shaped association between weight change categories and development of CKD was observed after adjustment for age, baseline GFR, baseline BMI, HDL, fasting blood glucose, uric acid, and exercise habits. The lowest risk for CKD was observed among those whose weight changed -0.25 to <0.25 kg/yr (P < 0.001 for quadratic term). Weight change as a time-dependent variable was significantly related to CKD incidence. These relationships remained significant even after further adjustment for Homeostasis Model Assessment of Insulin Resistance, high-sensitivity C-reactive protein, systolic BP, diastolic BP, metabolic syndrome, incident hypertension, or incident diabetes. In summary, increases in body weight are independently associated with an increased risk for CKD, even when the BMI remains within the normal range.