TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p<10-4), abnormal cytogenetics (median OS 14.4 months vs 33 months, p=0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p=0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p=0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.