We studied the effects of recombinant, interferon, 12‐O‐tetradecanoylphorbol13‐acetate (TPA), and phorbol 12,13 dibutyrate (PDB) on surface immunoglobulin expression by Daudi cells. Incubation of cells with recombinant alpha2interferon (IFN‐α2) caused a 2.5‐fold (60%) decrease in slgM expression as measured by relative fluorescence index (RFI) using a flow cytometer. This decrease in slgM expression was independent of inhibitory effects on proliferation and cell cycle progression. TPA or PDB also caused a threefold (67%) decrease in slgM expression, while enhancing proliferation and cell cycle progression. Coincubation of cells with IFN‐α2 or TPA decreased slgM expression by more than fourfold (>75%), which was greater than the decrease induced by the optimal concentration of either agent alone. Molecular studies demonstrated that the treatment of cells with IFN‐α2 or TPA decreased the steady‐state levels of mRNA for the heavy chain of IgM (cμ), suggesting that down‐regulation of slgM occurred at a pretranslational level. Activation of the cell membrane sodium/proton antiport did not play an integral role in the IFN‐α2 or phorbol‐ester‐induced pathway of slgM down‐regulation. Whereas IFN‐α2 induced an increase in the activity of 2′,5′‐oligoadenylate (2–5A) synthetase, the addition of TPA to IFN‐α2 caused a significant decrease in the activity of this enzyme. Although IFN‐α2 and TPA exhibited additive effects on slgM expression, they had opposing effects on cell proliferation, cell cycle progression, and induction of 2–5A synthetase activity, suggesting that these agents down‐regulate slgM expression through independent pathways.