The effect of recombinant human interferon-beta on growth and oncoprotein expression was investigated in several human breast-cancer cell lines with different characteristics. All cell lines tested were sensitive to the antiproliferative action of the drug, regardless of their estrogen sensitivity. The maximal inhibition of cell proliferation was seen after 6 days of treatment. In estrogen-sensitive CG-5 and ZR-75-1 cells, but not in MDA-MB-453 estrogen-insensitive cells, a reduction in c-myc and c-erbB2 oncoproteins occurred after 48-72 hr and became more pronounced after 120-168 hr of treatment, suggesting that this down-regulation is not direct but is mediated by undefined molecular mechanisms. The time-course of the IFN-mediated decrease in oncoproteins seems to indicate that this event is not strictly related to the IFN-regulation of cell proliferation. The expression of c-erbB2 and c-myc was also analyzed, after recombinant human interferon-beta treatment, at the mRNA level in CG-5 cells. Surprisingly, no statistically significant variation of c-erbB2 or of c-myc mRNA was found either before or after 120-168 hr. Thus, we surmise that the observed reduction of oncoproteins may be due to post-transcriptional mechanisms.