We examined the effects of eight subtypes of human interferon-alpha (IFN-alpha) and human IFN-beta on primary human B cells. In costimulation with antibodies to IgM (but not to CD40), some of these induced the cells to proliferate (but not to differentiate). Individual IFN differed greatly in their relative proliferative effects. IFN-alpha8 at 0.1-0.5 ng/ml induced proliferation, whereas most other subtypes were active only at concentrations >5 ng/ml, and IFN-alpha1 was inactive. These marked differences were not due to a selective overall increase in B cell response only to some IFN subtypes, as all those tested similarly induced the IFN-inducible genes 6-16 and HLA class I. Our results show that human B cells must respond to type I IFN via two distinct pathways. One is specific for IFN-alpha8 but can be activated by other IFN at relatively high concentrations. The other responds to them all and causes activation of IFN-inducible genes.