Atherosclerosis is the process responsible for our national epidemic of coronary heart disease. A primary and proven atherosclerotic risk factor is the plasma cholesterol concentration. Yet, proof that a reduction in plasma cholesterol level results in reduction in the incidence or severity of atherosclerosis and atherosclerotic cardiovascular disease stil requires conclusive documentation. The controversial methods of operation and inconclusive results of concluded first and second generation trials are reviewed. These data clearly demonstrate that a definitive test of the lipid hypothesis has not been reported. Evidence is presented to show that the partial ileal bypass operation most nearly fulfills the six features of an "ideal" lipid lowering trial modality: maximum effectiveness (∼50% cholesterol reduction); known mechanism of action; no response "escape" or "rebound"; obligatory effect without patient cooperation; minimal side effects; and relative safety. The basic design and protocol of the National Heart and Lung Institute Program on Surgical Control of the Hyperlipidemias, a secondary intervention trial using a combination of diet therapy and partial ileal bypass surgery, are outlined.