The croton oil-derived tumour-promoting agent 12-O-tetra-decanoyl-phorbol-13-acetate (TPA) exerts pleiotropic effects on the differentiation and proliferation of both normal and malignant animal and human cells in vitro. TPA is mitogenic in nanomolar concentrations to chicken embryo fibroblasts¹ and human T lymphocytes² and inhibits the terminal differentiation of various committed embryonic cells^3,4 and mouse Friend erythroleukaemia⁵ or myeloid leukaemia⁶ cells. TPA induces a terminal cell differentiation in some murine⁷ and human^7–11 myeloid leukaemia and histiocytic lymphoma cells¹². We report here the effect of TPA on chronic lymphocytic leukaemia (CLL) biopsy cells in vitro. In four out of five CLL patients studied, TPA induced the appearance of 90–100% lymphoblastoid and plasmacytoid cells after 4 days of culture. Under the influence of TPA, 86–97% of the cells expressed with time increasing amounts of intracytoplasmic immunoglobulin (C-Ig) of the same phenotype as that detected on the surface (S-Ig) of fresh, non-induced CLL cells. A parallel decrease in both monoclonal S-Ig density and DN A synthesis of the CLL cells was observed. Electron microscopic studies showed a maturation towards plasma cells. We therefore conclude that TPA is capable of inducing differentiation of CLL cells in vitro.