MORBIDITY AND MORTALITY RELATED TO GASTRIC BYPASS SURGERY: This 4-year renewal application will test the hypothesis that Roux-en-Y gastric bypass (RY-GBP) surgery reduces long-term (5 1/2-year follow-up) morbidity from severe obesity. This will be the first long-term controlled study of this procedure, which has tripled in use over the last 4 years and now comprises 93% of bariatric surgery in the U.S. In contrast to gastric banding, RY-GBP appears more likely to be associated with sustained weight loss and reduced morbidity at 5 years. Proof that RY-GBP produces long-term beneficial effects and reduces morbidity must be obtained before we can recommend the widespread use of this treatment for obesity. This is of urgency due to the rising epidemic of obesity and its sequelae (diabetes, hypertension, dyslipidemia, atherosclerosis), and due to the continuing absence of other effective long-term treatments for severe obesity. A 5 1/2-year follow-up is proposed in 924 severely obese subjects: 332 RY-GBP subjects, 336 control severely obese subjects seeking surgery but denied insurance coverage, and 256 random population severely obese controls. In the initial portion of this study, extensive characterization of these subjects at baseline and 2 years later (near the point of the greatest weight loss in the surgical subjects) was performed, including: body weight and composition, blood pressure, lipid profile, insulin resistance, resting metabolic rate, renal function, sleep apnea, echocardiogram, baseline and stress ECG, exercise treadmill fitness, physical activity, diet, and quality of life. All variables will be remeasured at 5 1/2 years to see if the 2-year morbidity reduction is maintained or further improved. Particular emphasis of the 5 1/2-year follow-up will be on echocardiographic changes that might lead to heart failure in the controls but be reversed in the surgical subjects. The 2-year follow-up suggests beneficial effects of RY-GBP on cardiac structure and function;however, these changes may continue to evolve for several years. The proposed study which would be the largest of it's kind to date, will provide a wealth of data crucial for surgeons, their patients and policy makers regarding the long-term risks and benefits of RY-GBP surgery.