Hepatosplenic γδ+ T-cell lymphoma represents a rare neoplasm of post-thymic phenotype, characterized by an aggressive clinical course and a poor response to conventional chemotherapy. In the present study, we have examined the cytotoxic effects of the purine analogue 2′-deoxycoformycin (dCF) on cultured mononuclear cells and purified γδ+ tumour cells from bone marrow or peripheral blood of four patients with hepatosplenic γδ+ T-cell lymphoma. At a concentration of 10 µm, dCF, in the presence of 2′-deoxyadenosine (dAdo), displayed an early and selective cytotoxic effect on γδ+ tumour T cells. After 48 h of in vitro exposure to dCF, the absolute number of viable CD3+/γδ+ tumour T cells was reduced by more than 90% in all samples with respect to control cultures, with absolute counts of viable CD3+/αβ+ lymphocytes being reduced only by 6–40% of the initial cell input. Analysis of cultures after 5 d of exposure to dCF plus dAdo revealed the persistence of normal CD3+/αβ+ T cells, which accounted, however, for only 20–25% of the initial cell input. Accordingly, the combination of dCF (10–100 µm) plus dAdo was able to induce a dose-dependent inhibition of clonogenic growth and [3H]-thymidine incorporation in purified CD3+/CD4−/CD8−γδ+ tumour cells. We also report that one patient with hepatosplenic γδ+ T-cell lymphoma in terminal leukaemic phase showed a striking haematological response to single-agent dCF given as fourth-line treatment. In particular, the selective clearance of γδ+ tumour T cells in peripheral blood and bone marrow was observed starting after the second course of treatment. Our results suggest that dCF may represent a potentially active drug for the management of this aggressive form of T-cell lymphoma.