p53 inactivation is a key factor in human tumorigenesis and chemotherapy resistance. The traditionally described mechanisms of p53 inactivation in acute myeloid leukemia (AML) include TP53 mutations and abrogation of p53 pathway. Malfunction of wild-type (wt) p53, due to its cytoplasmic mislocalization, has been described, thus far, only in solid tumors. Herein, we present a patient with therapy-related resistant AML, monosomal karyotype, wt TP53, and cytoplasmic sequestration of p53 protein. Proposed mechanisms of p53 mislocalization and their probable clinical and therapeutic implications are discussed. In view of the relative rareness of TP53 mutations in AML, the cytoplasmic sequestration of p53 protein offers an additional inactivating mechanism, which might be more frequent than currently diagnosed. This notion warrants confirmation by prospective studies in large cohorts of patients. We recommend that evaluation of p53 subcellular localization and function should be included in the diagnostic work-up of AML with wt p53.