Angioimmunoblastic T cell lymphoma (AILT) is a rare lymphoma that is regarded as a clinicopathologic entity but shows considerable histomorphologic diversity, variable immunophenotypes and inconsistent T cell receptor (TCR) gene rearrangement. One hundred four paraffin blocks of AILT were investigated defining tumor cell lineage by triple immunostains with a confocal laser scanning microscope and correlating morphology, immunophenotype and TCRγ gene rearrangement to clinical outcome. Ninety-nine cases were CD4+, some of them showing a mixture of CD4+ and CD4− tumor cells. The remaining 5 specimens were CD3+/CD4−/CD8−. A considerable number of T cells of different subtypes could always be found, but even in 13 cases predominated by CD8+ cells, proliferation could be attributed to atypical CD4+ cells. TCRγ gene rearrangement was monoclonal in 48 cases (69%) among 70 tested. In 29 of these semi-quantitative gene scan analysis resulted in a median proportion of monoclonal peak of 35% of PCR-products. Clinical outcome was identical grouping patients by clonality of TCRγ, absence or presence of clear cell clusters and international prognostic index. We conclude that AILT is mainly derived from CD2+CD3+CD4+CD5+CD7− mature T-helper cells with varying expression and partial loss of detectable CD4. A significant number of non-neoplastic T cells (resting CD4+ T cells and activated small or medium-sized CD8+ lymphocytes) may coexist with a minor neoplastic T cell population. Clinicopathologic correlation suggests AILT to be a well defined homogeneous entity with poor prognosis. Currently no prognostic factors can be derived. © 2002 Wiley-Liss, Inc.