The design was that of a cross-sectional family study. The recruitment and screening of probands were conducted over a four-year period at the University of Texas at Dallas under separate funding. The recruitment and screening of first-degree relatives were carried out at Berkeley. Blood samples were obtained from relatives for LDL subclass analysis and for lipid and apoprotein determination. An interview was conducted to obtain demographic information and information on behavioral and environmental risk factors such as smoking, exercise, and diet. The data were used to determine whether LDL subclasses were genetically controlled in families with hypercholesterolemia due to overproduction of LDL or defective clearance of LDL particles. Segregation analysis of LDL subclasses in these two types of families was performed to search for a single major genetic locus and to simultaneously test for the influence of polygenes and environmental effects. The relationships between the LDL subclass phenotype characterized by a predominance of small, dense LDL and overproduction of apoprotein B and LDL clearance defects were investigated in family members. A determination was made as to whether an age-of-onset effect existed for the expression of LDL subclass phenotypes. Genetic-environmental interactions were also studied.