More than 1000 different mutations in the LDL receptor gene (LDLR) result in familial hypercholesterolemia (FH). The present study adds to the landscape of molecular heterogeneity of FH in Bulgaria the frequency and molecular characteristics of large LDLR rearrangements. The study was done on genomic DNA in a group of 32 unrelated patients with severe hypercholesterolemia (plasma total cholesterol level >8.50 mmol/l) by Southern blotting analysis. Three carriers of large LDLR rearrangements (frequency 0.09 +/- 0.04), and two novel mutations were found - a large inversion involving exons 4, 5 and 6, and a deletion about 4.0 kb of a fragment located between exons 4 and 8 of the LDLR.