Background: This study intends to determine the diagnostic and prognostic roles of hypermethylation of serum RASSF1A and protocadherin-10 promoters in females with breast cancer.Methods: This study enrolled 80 breast cancer patients and 80 apparently normal healthy controls. The promoter methylation status of serum RASSF1A and PCDH10 genes was investigated using methylation specific PCR.Results: We detected no hypermethylation of the two genes in serum DNA of normal healthy controls (100% specificity). Of the 80 patients, 50 (62.5% sensitivity) displayed hypermethylated RASSF1A, whereas 34 (42.5% sensitivity) showed hypermethylated PCDH10 and 64 (80% sensitivity) were hypermethylated in at least one of these two genes. A significant association existed between hypermethylated RASSF1A and axillary lymph node involvement. There was a significant association between hypermethylated PCDH10 and axillary lymph node involvement, tumor size and pathological grade. Hypermethylated RASSF1A and PCDH10 combination was significantly associated with axillary lymph node involvement and Her-2 expression. Patients with methylated RASSF1A or PCDH10 had significantly shorter survival rates compared to those with unmethylated RASSF1A or PCDH10.Conclusion:Methylated RASSF1A is superior to methylated PCDH10 for diagnosis of breast cancer patients. Addition of methylated PCDH10 to methylated RASSF1A significantly improves the diagnostic accuracy of RASSF1A. The present study suggests that hypermethylated RASSF1A and PCDH10 may be independent prognostic indicators for disease-free survival in breast cancer patients.