The traditional lipid profile compared with nuclear magnetic resonance (NMR) may underestimate the risk for cardiovascular disease and may explain some of the discrepancies in results between studies analyzing the salubrious effects of soy. Our purpose was to compare the traditional lipid profile with NMR quantification of the number of lipoprotein particles, subclasses, and diameters or sizes in 30 sedentary males, between 18 and 30 years of age, consuming 1 of the following 3 supplements daily for 28 days: milk protein (Milk), isoflavone-poor soy protein (Soy-), or isoflavone-rich soy protein (Soy+). The study used a double-blind, parallel-arm design with random assignment to 1 of the 3 protein supplement groups. Fasting EDTA blood samples were collected at baseline and after 28 days of supplementation and analyzed for the number and size of very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particles, respectively. Fasting serum samples were analyzed for concentrations of total cholesterol (TC), LDL cholesterol (LDL-C), total HDL cholesterol (HDL-C), HDL(2)-C, HDL(3)-C, triglycerides (TGs), free fatty acids (FFAs), and glucose. Fasting heparin blood samples were collected at baseline and after supplementation and analyzed for apolipoproteins A-I, A-II, B, C-II, C-III, and E, as well as hepatic and lipoprotein lipase concentrations. HDL3-C increased by 47.2% after Soy+ supplementation and hepatic lipase decreased 19.2% after Soy- supplementation (p < 0.05). HDL-C and apolipoproteins A-I and A-II were found to increase in all 3 groups (p < 0.05). Results support that NMR analysis of lipoprotein particle number and size are not more sensitive to the effect of soy protein on CVD risk compared with the traditional lipid profile. Furthermore, the lack of isoflavones in soy protein seems to have a deleterious effect on hepatic lipase.