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The effect of tamoxifen (TX; 1.0 μM) on the mitogenic response of rat lymphocytes was compared with the effect of drugs that are known to act on protein kinase C (PKC), calmodulin (CM), and calcium (Ca²⁺). The calcium ionophore A23187 (0.2 μM) was mitogenic on its own which was not influenced by TX. The agents modulating PKC or CM (phorbol-myristate-13-acetate; R24571, chlorpromazine) influenced mitogenesis differently than did TX. General inhibition of lymphocyte proliferation was seen with the Ca²⁺ antagonist agents (EGTA, TMB-8) as with TX. The antiproliferative effect of TX was partially reversed by the increase of Ca²⁺ in the culture medium when T cell mitogens were used, but not in the case of lipid A, a B lymphocyte mitogen. However, the concanavalin A-induced Ca²⁺ influx was further elevated by TX which differed from the effect of the Ca²⁺ channel-blocking agent verapamil. The results suggest that TX resets the threshold stimulus necessary for mitogenesis and is completely reversible.