The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of TP53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematological malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, according to International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio: 4.47, 95% confidence interval: 1.64-12.2; P=0.0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.