The t(10;11)(p13-14;q14-21) associated with CALM-AF10 is considered to be rare and associated with a variety of acute lymphoid and myeloid leukemias. Twelve (9%) of 131 unselected T-cell acute lymphoid leukemias (T-ALLs) expressed CALM-AF10 by reverse transcription–polymerase chain reaction or fluorescence in situ hybridization (or both), including 8% of children and 10% of adults, of whom only half demonstrated a t(10;11) by classical cytogenetics. CALM-AF10 was not found in T-cell–receptor αβ (TCRαβ) lineage T-ALLs, as defined by expression of TCRαβ, cytoplasmic TCRβ, or TCRβVDJ rearrangement in immature cytoplasmic TCRβ^- cases, compared with 19% of TCRγδ T-ALLs and 33% of immature δ/γ T-ALLs. The latter differed from their CALM-AF10^- immature counterparts by a CD5⁺/CD2^-phenotype, as found in TCRγδ but not TCRαβ T-ALLs and in their TCRγ and TCRδ configurations, altogether suggesting that CALM-AF10⁺ immature δ/γT-ALLs are TCRγδ precursors and that, within T-ALL, CALM-AF10 is specific for this lineage. Nine of 12 immature CALM-AF10 T-ALLs demonstrated 3′ fusion transcripts, whereas 6 of 7 TCRγδ T-ALLs demonstrated 5′ fusion transcripts. The latter retain the AF10 extended LAP/PHD domain necessary for homo-oligomerization. All 8 patients with CALM-AF10⁺TCRγδ T-ALLs are alive, compared with only 3 of 12 with immature CALM-AF10⁺ T-ALLs. Six CALM-AF10⁺ non-T acute leukemias all expressed CD7 and demonstrated T-restricted TCRδ rearrangements, suggesting that they may also be related to the TCRγδ lineage. CALM-AF10 is therefore the most common fusion protein in T-ALL. It requires molecular and immunophenotypic characterization for appropriate prognostic evaluation and should be included in diagnostic screening panels of T-ALL and immature acute leukemias. Analysis of immature CALM-AF10⁺ leukemias will also facilitate analysis of the early stages of development of the TCRγδ lineage.