Pseudomonas exotoxin A has been implicated as a possible virulence factor in Pseudomonas infections. This toxin has a direct cytotoxic effect on a number of cell types, including macrophages and their precursors, and therefore may affect other cells of the immune system. NFR/N(H-2q) (+/nu or nu/nu) mice were immunized with either T-dependent or T-independent antigens along with various doses of exotoxin A. The immune response was then assayed by a modification of the Jerne plaque assay. Exotoxin A induced a dose-dependent suppression of the in vitro and in vivo immune responses to T-dependent and T-independent antigens in immunocompetent +/nu mice. However, in NFR/N nu/nu mice, suppression of the immune response to the T-independent antigen trinitrophenylated-Ficoll was not observed. Instead, a marked enhancement of the response was observed at doses of 100 and 10 ng of exotoxin A. Removal of T-cells with anti-Thy 1.2 antiserum plus complement before antigen and exotoxin A stimulation in +/nu mice results in abrogation of the suppression. These data suggest that Pseudomonas exotoxin A exerts an effect on both B- and T-lymphocyte populations to modulate the immune response and that this activity may be one facet of the pathogenic effects of this toxin.