The induction of polyclonal immunoglobulin (Ig) synthesis by glucocorticosteroids (GCS) in human peripheral blood lymphocytes is dependent on both T cells and monocytes. T cells can be replaced by a cytokine, T cell replacing factor for steroids (TRF-S), which promotes GCS-induced Ig production. T cells produce the cytokine when cultured with intact monocytes, with 24 hr monocyte supernatants, or with small quantities (0.1 U/ml or more) of highly purified interleukin 1 (IL 1). TRF-S was produced by isolated T4+ cells, whereas isolated T8+ cells were unable to help GCS-induced Ig synthesis. High pressure liquid chromatography with a gel permeation column revealed a single locus of activity that corresponded to an apparent m.w. of 40,000. At the dilutions utilized in culture, supernatants containing optimal TRF-S activity (3 U/ml final concentration in culture) were found to have less than 0.2 U/ml (final concentration) of interleukin 2 (IL 2) activity. Neither recombinant IL 2 nor recombinant interferon-gamma (IFN-gamma) over a broad range of concentrations was able to reproduce the capacity of TRF-S to induce the development of Ig-secreting cells with GCS. Thus, we report that TRF-S is synthesized primarily by T4+ T cells, and that its production is stimulated by small concentrations of IL 1. The apparent m.w. of TRF-S is 40,000, and its biological activity is distinct from that of IL 1, IL 2, and IFN-gamma.