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Promoter hypermethylation of circulating cell DNA has been advocated as a diagnostic marker for prostate cancer, but its prognostic use is currently unclear. To assess this role, we compared hypermethylation of circulating cell DNA from prostate cancer patients with (Group 1,n= 20) and without (Group 2,n= 22) disease progression and age-matched controls (benign prostatic hyperplasia, Group 3,n= 22). We measured hypermethylation of 10 gene promoters in 2 sequential venous samples, obtained at diagnosis and during disease progression (median time, 15 months later). Matched time samples were obtained in the nonprogressing patients. We found that more hypermethylation was detected in the diagnostic sample from the patients with cancer than in controls forGSTP1,RASSF1a,APCandRARβ(p< 0.0001). Patients undergoing disease progression had a significant increase in methylation levels of these 4 genes when compared to the other patients (p< 0.001). Patients at risk of disease progression have higher detectable concentrations of circulating cell hypermethylation, than those without progression. The extent of this hypermethylation increases during disease progression and can be used to identify the extent and duration of treatment response in prostate cancer.