Toxic-shock syndrome toxin-1 (TSST-1), a nonspecific T lymphocyte mitogen, was shown to cause the suppression of immunoglobulin-secreting cells (ISCs) generated in pokeweed mitogen (PWM)-stimulated cultures of human peripheral blood mononuclear cells (PBMs). Greater than 90% suppression of the PWM-stimulated ISC response was achieved when 2 X 10(6) PBMs were cultured in the presence of 1 microgram of TSST-1. The nonspecific suppression induced by the toxin was dose related; amounts of TSST-1 as low as 1.0 ng/2 X 10(6) cultured cells caused significant suppression of the ISC response. TSST-1-induced suppression was due to the activation of a population of cells that secreted a soluble factor that mediated the resulting suppression. PBMs were activated by a 24-hr preincubation of 2 X 10(6) cells in the presence of 1 microgram of TSST-1 followed by repeated washing to remove residual toxin. These cells, when co-cultured with unstimulated PBMs and PWM, suppressed the normal ISC response. The supernatant factor, active at volumes of 10 microliters/2 X 10(6) PBMs, was generated by harvesting the supernatant fluid of TSST-1-activated cells. The results of these in vitro experiments confirm that TSST-1 is an immunosuppressing agent that affects human lymphocyte function and, in such a capacity, may play a role in the development of toxic shock syndrome in humans.