Fifty-four unselected acute non-lymphocytic leukemias (ANLL) were analyzed for their immunophenotype, especially the expression of terminal deoxynucleotidyl transferase (TdT), as well as for rearrangements and/or deletions in the immunoglobulin heavy (IgH), Ig kappa, Ig lambda, T-cell receptor (TcR)-beta, TcR-gamma and TcR-delta/alpha genes. In 15% (8/54) of the ANLL patients one or more genes were rearranged. This especially concerned IgH gene rearrangements (seven cases) and to a lesser extent rearrangements of Ig kappa genes (one case), TcR-beta genes (three cases), TcR-gamma genes (two cases) and TcR-delta genes (two cases). Combined results from this study and from literature data on 378 unselected ANLL revealed that IgH gene rearrangements occurred in 14% of ANLL and Ig kappa gene rearrangements in 2% of ANLL patients. Rearrangements of Ig lambda genes have never been reported. Rearrangements of TcR-beta genes, TcR-gamma genes and TcR-delta genes have been found in 7, 5, and 9% of ANLL, respectively. In this study it was not possible to demonstrate an association between the presence of a TdT+ leukemic subpopulation and the occurrence of cross-lineage Ig or TcR gene rearrangements in ANLL. These rearrangements were detected in 13% (5/38) of ANLL with a TdT+ leukemic subpopulation and in 19% (3/16) of TdT- ANLL. Review of these data and over 400 published ANLL cases in which at least two different Ig and/or TcR genes had been investigated revealed that cross-lineage rearrangements of these genes concur frequently. Ig kappa gene rearrangements were only found in ANLL with rearranged IgH genes, whereas TcR-beta genes and TcR-gamma genes were only rearranged in combination with rearranged TcR-delta genes and/or IgH genes. Based on these data, an ordered pattern of cross-lineage Ig and TcR gene rearrangements in ANLL can be postulated, in which rearrangements of IgH genes or TcR-delta genes precede the other cross-lineage rearrangements.