4-Hydroxynonenal is a highly reactive aldehyde, produced by cellular lipid peroxidation, able to inhibit cell proliferation "in vitro" and "in vivo". Its concentration in non proliferating cells ranges up to 1 microM, whereas in the highly undifferentiated tumour cells, it is very low or undetectable. We have now demonstrated that micromolar concentrations of 4-hydroxynonenal inhibit c-myc but not N-ras expression in HL-60 human leukemic cells. This inhibitory effect is observed after an incubation of 1 hour with both 1 and 10 microM aldehyde. Moreover, we report that down-regulation of c-myc expression increases when repeated additions of 1 microM 4-hydroxynonenal are performed, to maintain the cells in presence of aldehyde for 7.5 hours. These results indicate that not only the concentration but also the length of exposure to the aldehyde is important in determining the extent of the c-myc expression inhibition and suggest a role of lipid peroxidation products in the control of gene expression.