Lipid and lipoprotein responses to reduced dietary fat intake were investigated in relation to differences in distribution of low-density-lipoprotein (LDL) subclasses among 105 healthy men consuming high-fat (46% fat) and low-fat (24% fat) diets in random order for 6 wk each. With high-fat diets, 87 subjects had predominantly large, buoyant LDL (pattern A), whereas the remainder had primarily smaller, denser LDL (pattern B). With low-fat diets, 36 men changed from pattern A to B. Compared with the 51 men with pattern A with both diets (stable A group), men in the stable B group (n = 18) had significantly greater reductions in plasma LDL cholesterol, apolipoprotein B, and mass of mid-sized (LDL II) and small (LDL III) LDL subfractions. In both the stable A and change groups, there was a shift in LDL particle mass from larger, lipid-enriched (LDL I and II) to smaller, lipid-depleted (LDL III and IV) subfractions, suggestive of change in LDL composition with minimal change in particle number, and consistent with the observation of reduced plasma LDL cholesterol without reduced apolipoprotein B. Stable B subjects had significantly greater increases in the largest very-low-density-lipoprotein subfraction with the low-fat diet than the stable A group, and also had greater decreases in the high-density-lipoprotein (HDL) subclass HDL3 but smaller reductions in HDL2. Genetic and environmental factors influencing LDL subclass distributions thus may also contribute substantially to interindividual variation in plasma lipoprotein response to a low-fat diet.