Context: Reduced intake of saturated fat is widely recommended for prevention of cardiovascular disease. The type of macronutrient that should replace saturated fat remains uncertain. Objective: To compare the effects of 3 healthful diets, each with reduced saturated fat intake, on blood pressure and serum lipids. Design, Setting, and Participants: Randomized, 3-period, cross-over feeding study(April 2003 to June 2005)conducted in Baltimore, Md, and Boston, Mass. Participants were 164 adults with prehypertension or stage 1 hypertension. Each feeding period lasted 6 weeks and body weight was kept constant. Interventions: A diet rich in carbohydrates; a diet rich in protein, about half from plant sources; and a diet rich in unsaturated fat, predominantly monounsaturated fat. Main Outcome Measures: Systolic blood pressure and low-density lipoprotein cholesterol. Res ults: Blood pressure, low-density lipoprotein cholesterol, and estimated corona ry heart disease risk were lower on each diet compared with baseline. Compared w ith the carbohydrate diet, the protein diet further decreased mean systolic bloo d pressure by 1.4 mm Hg(P=.002)and by 3.5 mm Hg(P=.006)among those with hyperten sion and decreased low-density lipoprotein cholesterol by 3.3 mg/dL(0.09 mmol/L ; P=.01), high-density lipoprotein cholesterol by 1.3 mg/dL(0.03 mmol/L; P=.02) , and triglycerides by 15.7 mg/dL(0.18 mmol/L; P< .001). Compared with the carbo hydrate diet, the unsaturated fat diet decreased systolic blood pressure by 1.3 mm Hg(P=.005)and by 2.9 mm Hg among those with hypertension(P=.02), had no signi ficant effect on low-density lipoprotein cholesterol, increased high-density l ipoprotein cholesterol by 1.1 mg/dL(0.03 mmol/L; P=.03), and lowered triglycerid es by 9.6 mg/dL(0.11 mmol/L; P=.02). Compared with the carbohydrate diet, estima ted 10-year coronary heart disease risk was lower and similar on the protein an d unsaturated fat diets. Conclusion: In the setting of a healthful diet, partial substitution of carbohydrate with either protein or monounsaturated fat can fur ther lower blood pressure, improve lipid levels, and reduce estimated cardiovasc ular risk. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT00051 350. Context: Reduced intake of saturated fat is widely recommended for prevention of cardiovascular disease. The type of macronutrient that should replace saturated fat remains uncertain. Objective: To compare the effects of 3 healthful diets, each with reduced saturated fat intake, on blood pressure and Serum lipids. Design, Setting, and Participants: Randomized, 3-period, cross-over feeding study (April 2003 to June 2005) conducted in Baltimore, Md, and Boston, Mass. Participants were 164 adults with prehypertension or stage 1 hypertension. Each feeding period lasted 6 weeks and body weight was kept constant. Interventions: A diet rich in carbohydrates; a diet rich in protein, about half from plant sources; and a diet rich in unsaturated fat, predominantly monounsaturated fat. Main Outcome Measures: Systolic Blood pressure and low-density lipoprotein cholesterol. Res ults: Blood pressure, low-density lipoprotein cholesterol, and estimated corona ry heart disease risk were lower on each die Compared w ith the carbohydrate diet, the protein diet further decreased mean systolic bloo d pressure by 1.4 mm Hg (P = .002) and by 3.5 mm Hg (P = .006) among those with hypertention and decreased decreased low-density lipoprotein cholesterol by 3.3 mg / dL (0.09 mmol / L; P = .01), high-density lipoprotein cholesterol by 1.3 mg / dL Compared with the carbo hydrate diet, the unsaturated fat diet decreased systolic blood pressure by 1.3 mm Hg (P = .005) and by 2.9 mm Hg among those with hypertension (P = .001) .02), had no signi ficant effect on low-density lipoprotein cholesterol, increased high-density lpoprotein cholesterol by 1.1 mg / dL (0.03 mmol / L; P = .03), and lowered triglycerids by 9.6 mg / dL 0.11 mmol / L; P = .02). Compared with the carbohydrate diet, estima ted 10-year coronary heart disease risk was lower and similar on the protein an d fat diets. Conclusion: In the setting of a healthful diet, partial substitution of carbohydrate with either protein or monounsaturated fat can fur ther lower blood pressure, improve lipid levels, and reduce estimated cardiovasc ular risk. Clinical Trials Registration: Clinical Trials.gov Identifier: NCT00051 350.