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Previous in vivo studies have shown that the immunsuppressive peptide cyclosporin A (CsA) selectively suppresses antibody responses to nonmitogenic T-independent (TI-2) antigens, but not those to mitogenic (TI-1) antigens. This report demonstrates that in vitro CsA suppresses the polyclonal proliferative response of B cells to anti-Ig (anti-mu) antibodies at 300-400 fold lower doses than are required to inhibit B cell proliferation induced by lipopolysaccharide. Since the proliferative response to anti-mu requires neither T cells nor macrophages, it is concluded that CsA has a direct inhibitory effect on the B cells responding to this mitogen. The data support the concept that the B cells responding to TI-2 antigens are contained within the population which is stimulated polyclonally by anti-mu, and that lipopolysaccharide stimulates a distinct B cell subpopulation. They do not, however, exclude the possibility that anti-mu and lipopolysaccharide stimulate the same B cell population via two biochemically distinct triggering mechanisms, one of which is CsA-sensitive and the other CsA-resistant.