Immunization with antigens stimulates not only B lymphocytes secreting specific antibody but, in addition, results in the generation of very large numbers of splenic Ig-secreting cells which lack specificity for that antigen. The present report examined the nature of the antigens capable of eliciting this effect and the mechanisms whereby B cells could be nonspecifically activated. It is shown that the ability of T-dependent, but not T-independent antigens, to induce such increases requires the participation of T helper cells specific for the antigen so that any one antigen results in the activation of only a proportion of total B cells. Analysis of this nonspecific plaque-forming-cell response reveals that B cell activation is not random but occurs in a class-restricted manner. The magnitude of the increase and the isotype produced are shown to be characteristic of the immunizing antigen. Based on the data presented, the apparent nonspecific T-B collaboration can best be explained by invoking a second Ig-specific helper mechanism in which helper cells capable of recognizing determinants on Ig molecules, e.g. isotype or idiotype, cause the stimulation of B cells of any specificity providing they express that determinant.