Higher-risk myelodysplastic syndromes (MDS) frequently progress to secondary AML (sAML) within months even in the presence of continuous therapy with azacitidine (AZA). Whether p53 expression status known to confer resistance to lenalidomide in low-risk del(5q) MDS might also influence response to therapy with AZA is unclear. We therefore analyzed the p53 expression in a cohort of 100 patients with higher-risk MDS or sAML treated with at least one complete cycle of AZA and correlated this to outcome. Thirty-five percent of patients were p53-positive and most had very poor risk cytogenetics with chromosome 5 aberrations and monosomal karyotypes. The overall response rate to AZA for patients for p53 positive and negative patients was 46% and 25%, respectively, P = 0.033). The median overall survival (OS) of the total cohort was 380 days with a median OS of 246 days for p53-positive patients and 410 days for p53-negative patients (not significant). In summary, in our cohort of 100 patients, the expression of p53 did not negatively impact on response to AZA. Although this analysis was not created for survival assessment it confirms the very poor survival for higher-risk MDS and sAML patients with high p53 expression despite response to AZA.