We have shown previously that yeast RNA preparations enhance in vitro antibody and Ig production to T-dependent antigens in normal B6 mice. In this study, Ig production by human peripheral blood mononuclear cells from adult volunteers was examined under RNA and mononucleotide-supplemented culture conditions. RNA significantly enhanced IgM and IgG production in a dose-dependent manner to pokeweed mitogen, T-dependent stimuli, and keyhole limpet hemocyanin modified with trinitrophenol, T-dependent antigens. IgM and IgG production in response to T-independent stimuli were not significantly altered by RNA and mononucleotides. IgA production appeared not to be influenced by RNA and mononucleotides irrespective of the stimuli provided. Interestingly, spontaneous IgM production also appeared to be enhanced by RNA. When RNA was degraded, oxidized, or decomposed of pyrimidine bases, this enhancing action of RNA on Ig production was considerably reduced. RNA was most effective when present from d 0 of the culture. Its enhancing action was lost when it was added at d 3 of the culture or later, when T cells were depleted, or when direct interactions between T cells and non-T cells were not permitted in the culture. Thus, RNA may enhance IgM and IgG production by human peripheral blood mononuclear cells to T-dependent stimuli partly by influencing the process of direct cellular interactions between T and non-T cells in the early stage of B-cell activation.