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Ten patients with large granular lymphocyte (LGL) leukemia were studied for rearrangement and expression of T cell receptor (TCR) genes. Eight patients with CD3 + LGL proliferation had unique TCR β-gene rearrangements, supporting a clonal process. Each of five patients studied with CD3 + disease had evidence for expression of full-length TCR α-, β-, and γ-gene transcripts. In contrast, patients with CD3- LGL proliferation had no evidence for rear- rangement or expression of TCR genes. These studies suggest that leukemic LGL arise from two different cell origins. Leukemic LGL may be a useful model for studying natural killer (NK) cell (CD3- LGL) and non-MHC-restricted cytotoxic T lymphocyte (CD3+ LGL) activation and differentiation.