Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemia, but it is unclear if this constitutes a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA positive cases among 209 adult T-cell acute lymphoblastic leukemia patients uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% v 14.5%, p = 0.0004), chemoresistance (59.3% v 40.8%, p = 0.026) and positive minimal residual disease (48.5% v 23.5%, p = 0.01) than the HOXA negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA positive cases harboring fusion onco-proteins that trans-activate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA positive group (5 year overall survival 31.2% in HOXA positive early thymic precursor v 66.7% in HOXA positive non-early thymic precursor, p = 0.03), but not in HOXA negative cases (5 year overall survival 74.2% in HOXA negative early thymic precursor v 57.2% in HOXA negative non-early thymic precursor, p = 0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (p = 0.053) and relapse risk (p = 0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia.