An IFN‐resistant subline (U‐266rα) was established from the IFN‐α‐sensitive myeloma cell line U‐266 by subculturing U‐266 cells with increasing doses of INF‐α. The U‐266rαsecreted IgE at a higher rate than the U‐266 (7.2 × 10−13g/c/8 h as compared to 3.3 × 10−13g/c/8 h). The 2 cell lines were found to be equally high producers of β2m (9.2 and 9.6 × 10−13g/c/8 h). The U‐266 produced 2.9 times less IgE and 5 times more β2m compared to the initial production rates at establishment. INF‐α and recombinant IFN‐αM2(rIFN‐α2) inhibited proliferation and concomitantly decreased the rate of IgE and β2m secretion in U‐266 but not in U‐266 IFNrα, which in contrast was slightly stimulated by IFN‐α with respect to growth, IgE and β2m secretion. In addition, IFN‐α at a concentration of 100 U/ml was shown to decrease the IgE and β2m production without exerting more than minimal cytotoxicity on U‐266 cells. No antiproliferative effect was found for IFN‐γ or recombinant IFN‐γ (rIFN‐γ) on either of the 2 cell lines. IFN‐γ and rIFN‐γ were, however, found to stimulate the production of β2m. Our results show that the U‐266 and the derived IFN‐α‐resistant subline can be used as models for studying some of the biological effects of IFN‐α and ‐γ in vitro. The clinical implications of these in vitro results, in particular the usefulness of serum determinations of