We studied the effect of recombinant interferon-alpha (IFN-alpha) on the proliferative response of normal human B cells and of lymphocytes from 10 patients with B cell-type chronic lymphocytic leukemia. We show that IFN-alpha, which has no effect on B cell proliferation when used alone, can synergize with anti-mu antibody and can support DNA synthesis by anti-mu activated B cells. This was observed with normal B cells and in 4 of 10 patients with B cell-type chronic lymphocytic leukemia. These four patients were all responders to B cell growth factor (BCGF), whereas the responsiveness to IFN-alpha was not correlated with that of IL-2. The positive functional relationship between IFN-alpha and BCGF in these patients is emphasized by the synergistic effect of these two factors in two of these patients, and the lack of inhibition of BCGF response by even supraoptimal concentrations of IFN-alpha. Among the subgroup of patients unable to respond to IFN-alpha, a synergy between IFN-alpha and IL-2 could be observed.