Background The DASH (Dietary Approaches to Stop Hypertension) diet is a carbohydrate-rich, reduced-fat diet that lowers blood pressure (BP) and LDL-cholesterol. Whether partial replacement of some carbohydrate (C) with either protein (P) or unsaturated fat (U) can further improve these and other cardiovascular (CVD) risk factors is unknown. Methods OmniHeart is a randomized, three-period, crossover feeding study designed to compare the effects on BP and blood lipids of a carbohydrate-rich diet (CARB, similar to the DASH diet) with a diet rich in protein (PROT, predominantly from nonmeat sources) and a diet rich in unsaturated fat (UNSAT, predominantly monounsaturated). Throughout feeding (run in and the three intervention periods), participants are provided with all of their meals that meet the nutrient profile of their assigned diet. Calorie intake is adjusted to maintain weight. The target sample size is 160 (50% African-American). Participants are adults, aged 30 or older, with prehypertension or Stage 1 hypertension (systolic BP 120–159 or diastolic BP 80–99 mmHg). The primary outcome variables are systolic BP and LDL-cholesterol. Secondary outcomes are diastolic BP, HDL-cholesterol, and triglycerides. Other outcome variables are total cholesterol, apolipoproteins VLDL-apoB, VLDL-apoCIII, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a), and insulin resistance, as measured by Homeostasis Model Assessment (HOMA). Conclusions OMNI-Heart should advance our fundamental knowledge of the effects of diet on both traditional and emerging risk factors, and, in the process, guide policy makers, health care providers and the general public on the relative benefits of carbohydrate, protein, and unsaturated fat as a means to reduce CVD risk.