Supernatants from peripheral blood mononuclear cells obtained from certain patients with the acquired immune deficiency syndrome (AIDS) or its prodrome were capable of depressing spontaneous and pokeweed mitogen-driven B lymphocyte differentiation into plasmacytes, and the proliferative responses of T cells to specific antigen. These soluble suppressor factors (SSF) were present in uniquely high concentrations, with significant differences from healthy controls and from patients with various other conditions previously associated with factor-mediated immunosuppression. T cell-independent functions were not modified by SSF. Suppression was not genetically constrained, and did not appear to be mediated by cytotoxicity, prostaglandin, or alpha or gamma interferons. SSF was a product of the interaction of T lymphocytes with adherent cells. T cells or T cell factors from AIDS patients, but not from normal controls, could collaborate with control adherent cells in the formation of SSF. Restoration of DNA synthesis-independent differentiation of B lymphocytes into plasmacytes in SSF-treated cultures was realized by addition of reducing agents, such as 2-mercaptoethanol, on culture initiation. These data suggest inhibitory mechanisms possibly related to that of concanavalin A-induced soluble immune response suppression, and perhaps offer clues to clinically applicable substances which are potentially capable of mitigating such responses.