The Healthy Eating Index (HEI), designed to assess adherence to the Dietary Guidelines for Americans and the Food Guide Pyramid, was previously associated with only a small reduction in major chronic disease risk in US adult men and women. We assessed whether an alternate index would better predict risk. Dietary intake reported by men and women from two prospective cohorts was scored according to an a priori designed Alternate Healthy Eating Index (AHEI). In contrast with the original HEI, the AHEI distinguished quality within food groups and acknowledged health benefits of unsaturated oils. The score was then used to predict development of CVD, cancer or other causes of death in the same population previously tested. 67,271 women from the Nurses' Health Study and 38 615 men from the Health Professionals' Follow-up Study. Men and women with AHEI scores in the top vs. bottom quintile had a significant 20% and 11% reduction in overall major chronic disease, respectively. Reductions were stronger for CVD risk in men (RR = 0.61, 95% CI 0.49-0.75) and women (RR = 0.72, 95% CI 0.60-0.86). The score did not predict cancer risk. The AHEI was twice as strong at predicting major chronic disease and CVD risk compared to the original HEI, suggesting that major chronic disease risk can be further reduced with more comprehensive and detailed dietary guidance.