p73, a tumor suppressor gene with significant homology to p53, is hypermethylated in a high percentage of NK-cell lymphoma and B-cell lymphomas patients. Given these data, we sought to study the role of p73 methylation in the pathogenesis of myelodysplastic syndromes (MDS). In this study, the methylation status of the p73 gene promoter was analyzed by methylation-specific polymerase chain reaction (MS-PCR) in bone marrow (BM) samples from 135 adult patients with de novo MDS. The results of MS-PCR were confirmed by bisulfite sequencing. We found that p73 methylation was present in 37% (n = 50) of these cases and methylaiton was correlated significantly with World Health Organization (WHO) subtypes. Patients with advanced stages of WHO subtypes (30 vs. 59%, P = 0.002) exhibited a significantly higher frequency of p73 methylation. Moreover, a decrease in transcription of p73 was accompanied by methylation (P = 0.032) and the decitabine treatment restored the expression of p73. The median survival of patients with p73 methylation was shorter than that for patients without p73 methylation (15 vs. >33 months, P = 0.002). A multivariate analysis also indicated that the p73 methylation status was the independent factor that impacted overall survival (OS) and leukemia-free survival (LFS). However, we failed to find any significant association between p73 methylation and clinical responses to decitabine, a hypomethylating agent that was approved by the US Food and Drug Administration for the treatment of patients with MDS. In conclusion, p73 methylation is common in patients with MDS and indicate poor prognosis. p73 may be a therapeutic target in MDS.