Some weight loss diets promote protein intake; however, the association of protein with disease is unclear. In 1986, 29,017 postmenopausal Iowa women without cancer, coronary heart disease (CHD), or diabetes were followed prospectively for 15 years for cancer incidence and mortality from CHD, cancer, and all causes. Mailed questionnaires assessed dietary, lifestyle, and medical information. Nutrient density models estimated risk ratios from a simulated substitution of total and type of dietary protein for carbohydrate and of vegetable for animal protein. The authors identified 4,843 new cancers, 739 CHD deaths, 1,676 cancer deaths, and 3,978 total deaths. Among women in the highest intake quintile, CHD mortality decreased by 30% from an isoenergetic substitution of vegetable protein for carbohydrate (95% confidence interval (CI): 0.49, 0.99) and of vegetable for animal protein (95% CI: 0.51, 0.98), following multivariable adjustment. Although no association was observed with any outcome when animal protein was substituted for carbohydrate, CHD mortality was associated with red meats (risk ratio = 1.44, 95% CI: 1.06, 1.94) and dairy products (risk ratio = 1.41, 95% CI: 1.07, 1.86) when substituted for servings per 1,000 kcal (4.2 MJ) of carbohydrate foods. Long-term adherence to high-protein diets, without discrimination toward protein source, may have potentially adverse health consequences.