It is well known that human lymphoblastoid interferon-alpha [HuIFN-alpha(ly)] may either increase or decrease antibody production by B cells, in vivo as well as in vitro, depending on the experimental conditions and the system used. We compare here the effect of HuIFN-alpha(ly) and human recombinant interferon-alpha (rHuIFN-alpha) on immunoglobulin M (IgM) production by secreting and nonsecreting human B-like lymphoblastoid cells, respectively, ST8246, and Daudi cells. Under our experimental conditions, Daudi cells were less sensitive to the antiproliferative effect of IFN than previously reported by other authors, and ST8246 cells were insensitive to this antiproliferative effect. In contrast, IgM production was profoundly affected in both cell lines. Thus, we could discriminate between the effect on cell growth from the effect on the immune response. Using high-pressure liquid chromatography (HPLC) separation, mu chains and monomeric and pentameric IgM were distinguished from cytosolic and membrane-associated fractions and from culture medium (extracellular IgM). Pentameric extracellular IgM and monomeric membrane IgM were diminished by HuIFN-alpha(ly) treatment, respectively, in ST8246 cells and in Daudi cells. We conclude that HuIFN-alpha(ly) induces regression of B-like lymphoblastoid cells toward a less mature phenotype.