OBJECTIVES: High-resolution melting analysis has been validated for screening several genes of clinical significance. We evaluated whether it would be useful for detecting mutations in the LDL receptor gene (LDLR). DESIGN AND METHODS: We analysed 60 samples heterozygous for different LDLR sequence variants, and compared the melting curves to those of the corresponding homozygous normal amplicons to assess whether they would be detected in a mutation scanning screen using melting analysis. RESULTS: Although six mutations in exon 4 did not yield usable melting data, 96% (52/54) of the other variants were detected by the melting analysis, while two variants were poorly resolved. CONCLUSIONS: Melting analysis is a rapid and sensitive mutation scanning technique, but is not suitable for some GC-rich amplicons such as LDLR exon 4, or exons with high frequencies of benign polymorphisms which would require follow-up DNA sequencing. We developed a successful strategy which combines melting analysis with direct sequencing of problematic amplicons.