Low-density lipoprotein (LDL) subclass pattern B is a common genetically influenced lipoprotein profile characterized by a predominance of small, dense LDL particles, and associated with increased levels of triglyceride-rich lipoproteins, reductions in high-density lipoprotein cholesterol (HDL-C), and increased risk of coronary artery disease compared to individuals with a predominance of larger LDL (pattern A). We sought to determine whether LDL subclass patterns are associated with response of plasma lipoprotein levels to changes in dietary fat and carbohydrate content. In a randomized cross-over study, 105 men consumed, for six weeks each, high-fat (46%) and low-fat (24%) solid food diets, with replacement of fat by carbohydrate. Diet-induced changes in subjects who exhibited pattern B (n = 18) following the high-fat diet differed significantly from those in subjects with pattern A (n = 87): in pattern B subjects LDL cholesterol (LDL-C) reductions were two-fold greater and plasma apolipoprotein (apo) B levels decreased significantly. These differences remained significant after adjustment for levels of plasma LDL-C, apo B, HDL-C, and body mass index. Thus, LDL subclass pattern is a factor that contributes significantly to interindividual variation of plasma lipoprotein response to a low-fat, high-carbohydrate diet.