A group of 218 patients with severe hypercholesterolemia (LDL cholesterol > 260 mg/dl) living in the Cologne area were screened for mutations in the LDL receptor gene and apolipoprotein B-100 gene. In the LDL receptor gene Southern blotting was used for detection of major DNA rearrangements and the single-strand conformation polymorphism (SSCP) method was used to screen for micro-deletions and insertions and single base alterations. The Arg3500-->Glu mutation, which is the only relevant mutation in the apolipoprotein B-100 gene causing hypercholesterolemia, was detected by a modified PCR and restriction enzyme digestion. Three different major rearrangements, all of which were deletion, were found in the LDL receptor gene. The SSCP screening was started with exon 4. In 20 cases an abnormal fragment pattern was observed. The apolipoprotein B-100 mutation was detected in 15 patients. In summary, by the combined analysis of major rearrangements, micro-deletions, insertions and single base alterations in the LDL receptor gene and the Arg3500-->Glu mutation in the apolipoprotein B-100 gene, mutations causing or probably causing hypercholesterolemia could be detected in 38 of the 218 studied patients. The expansion of SSCP screening to other exons of the LDL receptor gene will greatly increase the identification of mutations causing hypercholesterolemia.