Interferons (IFN) are known to modulate immune responses in either an inhibitory or a stimulating manner. The present study was initiated to investigate the mechanisms by which α-IFN modulates Ig production of human peripheral blood mononuclear cells (PBMC). IgG and IgM production was measured in pokeweed mitogen- (PWM) stimulated 7-day cultures of PBMC. Significant enhancement of IgM and IgG production was observed when α-IFN was added. Overnight preincubation followed by washing also produced significant enhancement. The effect of α-IFN was not obtained in the absence of PWM or T cells. The effect of α-IFN on cultures of B and T cells was not altered by irradiation of T cells (2000 rad). α-IFN was not shown to enhance the production of helper factor but did increase the responsiveness of B cells to helper factor if the B cells were preincubated with α-IFN. Finally, α-IFN did not increase the Ig production of PBMC induced by Epstein Barr virus (EBV), and the outgrowth of EBV-infected PBMC was not affected. Overall, these results show for the first time that the effect of α-IFN on PBMC is due to an enhanced responsiveness of B cells to helper factors produced by radioresistant T cells.