The Healthy Eating Index-2005 (HEI-2005) measures adherence to the 2005 Dietary Guidelines for Americans, but the association between the HEI-2005 and risk of chronic disease is not known. The Alternative Healthy Eating Index (AHEI), which is based on foods and nutrients predictive of chronic disease risk, was associated inversely with chronic disease risk previously. We updated the AHEI, including additional dietary factors involved in the development of chronic disease, and assessed the associations between the AHEI-2010 and the HEI-2005 and risk of major chronic disease prospectively among 71,495 women from the Nurses' Health Study and 41,029 men from the Health Professionals Follow-Up Study who were free of chronic disease at baseline. During ≥24 y of follow-up, we documented 26,759 and 15,558 incident chronic diseases (cardiovascular disease, diabetes, cancer, or nontrauma death) among women and men, respectively. The RR (95% CI) of chronic disease comparing the highest with the lowest quintile was 0.84 (0.81, 0.87) for the HEI-2005 and 0.81 (0.77, 0.85) for the AHEI-2010. The AHEI-2010 and HEI-2005 were most strongly associated with coronary heart disease (CHD) and diabetes, and for both outcomes the AHEI-2010 was more strongly associated with risk than the HEI-2005 (P-difference = 0.002 and <0.001, respectively). The 2 indices were similarly associated with risk of stroke and cancer. These findings suggest that closer adherence to the 2005 Dietary Guidelines may lower risk of major chronic disease. However, the AHEI-2010, which included additional dietary information, was more strongly associated with chronic disease risk, particularly CHD and diabetes.