Pseudomonas aeruginosa has been shown to suppress cell-mediated immunity in experimental animals, but recent reports have also demonstrated that there is a strong T-cell response to this bacteria. Our studies of human peripheral blood mononuclear cells showed a great variation in the in vitro proliferative response to killed P. aeruginosa, so we examined the interaction of the different mononuclear cells in cultures with this bacteria. P. aeruginosa stimulated the proliferation of T lymphocytes, specifically the surface-immunoglobulin-negative, T8- subset, which are felt to be T helper cells. P. aeruginosa added in coculture experiments to peripheral blood mononuclear cells stimulated with Staphylococcus aureus, Streptococcus pyogenes, or tetanus toxoid suppressed the proliferation to these latter antigens. This proliferation was not affected by the depletion of adherent monocytes from peripheral blood mononuclear cells, and the suppression was restored when monocytes were added back to these cultures. Moreover, monocytes pulsed with P. aeruginosa but not with S. aureus suppressed the antigen-induced proliferation of peripheral blood mononuclear cells. This monocyte suppression was not inhibited by indomethacin and was unlikely to be the result of prostaglandin synthesis by these cells. Thus, P. aeruginosa can induce monocytes to suppress antigen-stimulated T-lymphocyte proliferation in vitro, and these suppressor cells may facilitate the growth of this organism in disorders such as cystic fibrosis.