Multiple DNA microsatellites with frequent loss of heterozygosity (LOH) in melanomas have been demonstrated. The finding that free DNA is enriched in blood of melanoma patients prompted studies to determine whether tumor-specific DNA, such as DNA microsatellites exhibiting LOH, can be detected in blood and have clinical use. In this study, 57 advanced and 19 early clinically staged melanoma patients were assessed using 10 microsatellite markers on six chromosomes. Matched plasma and melanoma tissues from 40 patients showed significant concordance of LOH (P < 0.0001). The frequency of LOH microsatellite markers detected in plasma significantly increased in more advanced-staged patients. At locus D3S1293, LOH detection showed significant correlation to clinical disease progression (P = 0.02). Additionally, the combination of LOH microsatellite markers D9S157 and D3S1293 (P = 0.01), D9S157 and D1S228 (P = 0.05), and D11S925 and D3S1293 (P = 0.01) were significantly correlated to progression of different clinical stages of disease. These studies indicate that tumor-specific LOH markers in plasma have a potential clinical use as diagnostic and prognostic markers in melanoma patients.