Interleukin-6 (IL-6) is a late-acting differentiation factor for human B cells activated by polyclonal mitogens such as pokeweed mitogen (PWM) and Staphylococcus aureus Cowan strain I, but its role in specific antibody responses has not been established. We show here that IL-6 has no consistent effect on specific antibody responses by tonsillar mononuclear cells (TMC) stimulated with influenza virus. A blocking IL-6 antibody also had no effect on antibody production, suggesting that endogenous IL-6 production was not required. In control experiments, this antibody inhibited PWM-stimulated immunoglobulin secretion and proliferation of the IL-6-dependent B cell line B9. A requirement for IL-6 in responses of unfractionated TMC may have been disguised by the presence of T cells. To overcome this problem, we investigated the effect of IL-6 on specific antibody production by T-depleted B cells stimulated with antigen in the presence of IL-2, which is a T cell replacing factor (TRF) for human B cells. Specific antibody production was restored by IL-2, but not IL-6. Neither IL-6 nor anti-IL-6 antibody had any consistent effect on specific antibody production by purified B cells stimulated with antigen and TRF. These experiments show that IL-6 does not have a significant role in antigen (influenza virus)-specific antibody responses by human B lymphocytes.