We observed that Sendai virus preinduction of peripheral blood mononuclear cells and subsequent mitogenic stimulation resulted in: (i) Superproduction of interferon-gamma, (IFN-gamma) (ii) an increase in interleukin-2 (IL-2) synthesis that correlates with DNA synthesis when stimulated with phytohemagglutinin (PHA) or pokeweed mitogen (PWM) after treatment with the Sendai virus, while stimulation with Protein A from Staphylococcus aureus was not affected, and (iii) enhanced tumor necrosis factor-alpha (TNF-alpha) production in response to bacterial lipopolysaccharide (LPS). Treatment of monocyte cultures with LPS and cycloheximide or actinomycin-D inhibited the superinduction phenomenon. When cycloheximide was added at the viral induction time, the inhibition of TNF-alpha superproduction and DNA synthesis was still observed. These results suggest that Sendai virus lymphocyte superinduction is specific for a particular stimulatory pathway, not dependent on mRNA accumulation, and probably mediated by induction of an activating protein.