Adult T-cell acute lymphoblastic leukemia (T-ALL) continues to represent an unfavorable disease. Molecularly based treatment stratifications could help improve outcome. The prognostic impact of HOX11 and HOX11L2 expression has been an area of controversy. We have investigated 286 adult T-ALL patients enrolled into the German Multicenter ALL (GMALL) therapy protocols by comparative real-time RT-PCR. High HOX11 expression and HOX11L2 expression were predominantly seen in thymic T-ALL (P<or=0.031). In a multivariate analysis HOX11L2 expression proved to be an independent adverse risk factor for relapse-free survival (RFS) with a hazard ratio (HR) of 2.02 (P=0.023) and an HR for overall survival (OS) of 1.81 (P=0.021), both adjusted for the immunophenotype. HOX11 expression was found to have a favorable impact on RFS (HR 0.51; P=0.048) but did not exhibit a significant impact on OS. A subgroup analysis for thymic T-ALL revealed a more pronounced negative correlation of HOX11L2 expression with RFS (HR 3.26; P=0.002) and OS (HR 2.38; P=0.009). Although the prognostic impact of HOX11 in T-ALL is less clear, HOX11L2 expression identifies a small subset of high-risk patients, who are so far classified as standard-risk group. Thus, patients with aberrant HOX11L2 expression should be considered early as candidates for intensified treatment regimes.