Genomic mismatch scanning (GMS) is a high-throughput, high-resolution identity by descent mapping technique that enriches for genomic DNA fragments that are shared between related individuals. In GMS, DNA heteroduplexes are formed from restriction-digested genomic DNA fragments from two relatives. Mismatch-free DNA heteroduplexes, likely representing DNA shared identical by descent between the two individuals, are relatively purified by depleting the mismatch-containing heteroduplexes using the Escherichia coli mismatch repair proteins and exonuclease. Here, we demonstrate using quantitative microsatellite genotyping that, despite the complexity of the human genome, GMS can enrich the majority of restriction fragments that are identical by descent between two related humans. As the entire genome is selected in GMS, an extraordinarily dense set of markers (up to 200,000 markers) may be screened in parallel. The demonstration of the molecular enrichment of identical DNA fragments in the context of the whole human genome establishes conditions for the application of GMS to human genetics. This forms a frame-work for the further development of GMS as a hybridization-based mapping technique that utilizes DNA microarray technology to map the selected identical by descent DNA fragments.