Low concentrations (1-5 microM) of beryllium (Be) salts were weakly mitogenic to mouse spleen cells in vitro as measured by an hydroxyurea-sensitive 2-3fold increase in pulse labelled [3H]-thymidine incorporation into lymphocyte DNA. It is proposed the activation may be induced by a direct interaction of Be2+ with the lymphocyte membranes. Higher concentrations of Be2+ (5-20 microM) produced a gradual loss of the stimulatory response, possibly as the result of either a limited cytotoxic effect or by the established property of intracellularly-accumulated Be2+ to inhibit cell division. In contrast, Concanavalin A-stimulated lymphocyte mitogenesis was markedly decreased by a 20-h preincubation of splenocytes with micromolar concentrations of Be2+, whereas similar pretreatment with lower concentrations (0.1 microM) actually enchanced the subsequent proliferative response. In both cases, supplementary addition of 0.1-1% peritoneal macrophages increased the level of Concanavalin A stimulation. It is concluded, therefore, that inhibition of the proliferative response to accessory cell-dependent mitogens may result from dose-dependent destruction by Be2+ of the macrophage/adherent cell population.