The direct effects of interleukin-1 (IL-1), interleukin-2 (IL-2), alpha-interferon, and gamma-interferon on human B cell activation, proliferation, and differentiation have been examined and compared to the effects of B cell growth factor (BCGF) and B cell differentiation factor (BCDF). Human tonsillar B lymphocytes were separated according to cell size into two nonoverlapping and functionally distinct populations. The small fraction was incubated with IL-1, IL-2, alpha-interferon, or gamma-interferon, and subsequent DNA synthesis and immunoglobulin production were measured. None of the factors induced these cells to proliferate or to differentiate. Similarly, the large fraction of B cells was incubated with IL-1, IL-2, alpha-interferon, gamma-interferon, BCGF, or BCDF. BCGF augmented the proliferation, and BCDF augmented the differentiation of the large B cells. In comparison, IL-1, IL-2, alpha-interferon, or gamma-interferon had either a minor effect or no effect on large B cell proliferation and differentiation. Thus, this study suggests that IL-1, IL-2, alpha-interferon, and gamma-interferon are not important direct signals for mature B cell function when present in the absence of other signals.