It has recently been reported that c-myc is an inducible gene, regulated directly by growth signals which promote proliferation and expressed in a cell-cycle dependent manner¹. Because various leukaemic cell lines express high levels of c-myc messenger RNA², it was of interest to discover whether the gene could be down-regulated in these cells by a growth inhibitor such as interferon (IFN)³ We show here that in Daudi Burkitt's lymphoma cells, IFN-α produces a five- to sevenfold reduction in c-myc mRNA through a decreased rate of c-myc gene transcription. By isolating a growth-resistant Daudi cell variant that had escaped from this down-regulation, we provide the first clear link between reduction of c-myc mRNA and the IFN-mediated G₀/G₁ arrest characteristic of Daudi cells. Furthermore, by screening other cell lines, we demonstrate the heterogeneity of human leukaemic cells with respect to these criteria. Thus, IFN-α fails to reduce the c-myc mRNA and to change the cell-cycle distribution in HL-60 and U937 cells, although normal induction of other IFN-regulated activities takes place. The latter group of cells shows a decline in c-myc gene expression when they become arrested in the G₀/G₁ phase as part of their terminal differentiation.