Mouse spleen lymphocytes activated by a mitogenic concentration of concanavalin A (Con A) secrete a factor(s), termed soluble immune response suppressor (SIRS), which is a potent, noncytotoxic inhibitor of primary plaque forming cell (PFC) responses by mouse spleen cells to heterologous erythrocytes in vitro. SIRS activity was detected in supernatant fluids of spleen cell cultures within 6 hr of stimulation with Con A and was maximal from 12 to 24 hr after stimulation. SIRS profoundly suppressed 5 day PFC responses when added to antigen stimulated spleen cell cultures at initiation, was less effective when added 24 hr after initiation, and had no significant effect when added 48 or more hr after initiation. SIRS had to be present in antigen stimulated spleen cell cultures only during the initial 24 hr of incubation to cause suppression of PFC responses which by kinetic analysis was not manifest until 120 hr of incubation. Background and antigen stimulated IgM and IgG PFC responses were suppressed by SIRS. Exposure to SIRS did not render spleen cells totally incapable of developing PFC responses to heterologous erythrocytes. Instead, antigen stimulated PFC responses in control cultures and cultures containing SIRS had the same kinetics and were of comparable magnitude during the first 96 hr of incubation. Thereafter, however, PFC responses in cultures containing SIRS abruptly aborted and the SIRS induced suppression of PFC responses became evident at 120 and 144 hr of incubation. Although the precise mechanism(s) of action of SIRS is unknown, it appears to function during the early, antigen dependent phase of the immune response in vitro to abort full expression of the PFC response during the later exponential expansion of the clones of antibody synthesizing cells.