Epidemiologic studies and clinical trials have demonstrated that the unique fatty acid profile of nuts beneficially affects serum lipids/lipoproteins, reducing cardiovascular disease (CVD) risk. Nuts are low in SFA and high in PUFA and monounsaturated fatty acids (MUFA). Macadamia nuts are a rich source of MUFA. A randomized, crossover, controlled feeding study (5-wk diet periods) compared a Macadamia nut-rich diet [42.5 g (1.5 ounces)/8.79 MJ (2100 kcal)] [MAC; 33% total fat (7% SFA, 18% MUFA, 5% PUFA)] vs. an average American diet [AAD; 33% total fat (13% SFA, 11% MUFA, 5% PUFA)] on the lipid/lipoprotein profile of mildly hypercholesterolemic (n = 25; 15 female, 10 male) subjects. Serum concentrations of total cholesterol (TC) and LDL cholesterol (LDL-C) following the MAC (4.94 +/- 0.17 mmol/L, 3.14 +/- 0.14 mmol/L) were lower than the AAD (5.45 +/- 0.17 mmol/L, 3.44 +/- 0.14 mmol/L; P < 0.05). The serum non-HDL cholesterol (HDL-C) concentration and the ratios of TC:HDL-C and LDL-C:HDL-C were reduced following consumption of the MAC diet (3.83 +/- 0.17, 4.60 +/- 0.24, and 2.91 +/- 0.17, respectively) compared with the AAD (4.26 +/- 0.17, 4.89 +/- 0.24, and 3.09 +/- 0.18, respectively; P < 0.05). There was no change in serum triglyceride concentration. Thus, macadamia nuts can be included in a heart-healthy dietary pattern that reduces lipid/lipoprotein CVD risk factors. Nuts as an isocaloric substitute for high SFA foods increase the proportion of unsaturated fatty acids and decrease SFA, thereby lowering CVD risk.