Mercury-induced autoimmune disorders have been demonstrated in rats and mice injected with HgCl2. We have studied the ability of HgCl2 to activate murine lymphocytes in vitro and found that it induced increased DNA synthesis, which peaked at days 4 to 6. Other metal ions, such as Mg2+ and Zn2+, had no or much less effect. Consistent with the in vivo studies, there were strain differences, and the most significant increase in thymidine uptake was induced in A.SW and BALB/c spleen cells. Both T lymphocytes and adherent cells were required for activation, and anti-CD4 Ab completely abrogated HgCl2-induced proliferation, suggesting the involvement of T helper cells. Cell phenotype analysis demonstrated that HgCl2 induced both proliferation and transformation of CD4+ and CD8+ T cells from BALB/c mice (responder strain). In contrast, only CD8+ T cells from the nonresponder DBA/2 mice were transformed. These findings indicate that helper T cells play a crucial role for the immunologic effects caused by HgCl2 and determine the ability of different mouse strains to respond to HgCl2.