Dietary Guidelines for the promotion of overall good health and the prevention of disease often play an important role in setting nutritional policy and in the education of the public about healthy food choices. Although much has been written about adherence to such guidelines, until recently there was no evidence on whether adherence to specific dietary guidelines is associated with better health. As an outcome variable for such analyses, we have used the incidence of major chronic disease, which includes incidence of any major cardiovascular disease, cancer, or death from any cause excluding violence. We have evaluated the Dietary Guidelines for Americans using a scoring system called the Healthy Eating Index developed by the Department of Agriculture to quantify adherence to these guidelines. We found that adherence to the Dietary Guidelines and the Food Guide Pyramid was associated with only a small reduction in major chronic disease risk in a population of over 100,000 US adult men and women. We also assessed whether an alternate index, which took into account the type of fat and quality of carbohydrate, would better predict risk. In contrast with the original Healthy Eating Index, adherence to the alternative index predicted lower rates of major chronic disease, and particularly cardiovascular disease, suggesting that the Dietary Guidelines were not offering optimal dietary guidance. These analyses suggest that dietary guidelines should be evaluated for their ability to predict the occurrence of major illness, and that such analyses can help refine these guidelines.