The effect of cyclosporin A on the induction and activation of B memory cells by thymus-independent (TI) antigens was investigated. Studies were carried out in C57BL/6 mice, a strain in which TI.1 trinitrophenyl-lipopolysaccharide (TNP-LPS) and TI.2 dinitrophenyl-(DNP)-Ficoll antigens can elicit a secondary response. Evidence is presented that cyclosporin A does not adversely affect the primary or secondary response to TNP-LPS. In contrast, this fungal metabolite prevents the triggering of virgin B lymphocytes and TNP-LPS-induced memory cells by DNP-Ficoll. Cyclosporin A does not interfere with the generation of hapten-specific B memory cells by TNP-LPS or DNP-Ficoll. These findings are discussed in terms of B cell lineages leading to antibody-forming cell precursors and memory cells.