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The immunosuppressive effects of methyl mercury (MH), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) are well established at high exposure levels but unclear at low exposure levels. We exposed Fischer 344 rat splenocytes, thymocytes, and peripheral blood lymphocytes in vitro for 72 h to MHg (0.1, 2 μg/ml), PCDD/PCDF mixtures (1, 15 pg/ml) of three PCDDs (2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,7,8-pentachlorodibenzo-p-dioxin, and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin) and two PCDFs (2,3,7,8-tetrachlorodibenzofuran and 1,2,3,7,8-pentachlorodibenzo-furan), three Aroclor® (1242, 1254, 1260), PCB mixtures (0.01, 0.5 μg/ml), or combinations of MHg/PCB/PCDD/PCDF mixtures Mitogenic responses of lymphocytes to concanavalin A, phytohemagglutinin, or lipopolysaccharide/dextran sulfate were determined by 3H-thymidine uptake; cytotoxicity and intracellular Ca2+ were determined by flow cytometry. Methylmercury (2 μg/ml and PCB/ PCDD/PCDF mixtures with 2 μg/ml MHg decreased the viability of splenocytes to 57 and 40% at 4 and 24 h, respectively. Basal intracellular calcium ion levels were unaffected by the treatments. Methylmercury suppressed the responses of lymphocytes to T and B cell mitogens. All combinations of MHg/PCB/PCDD/PCDF mixtures decreased mitogenic responses to levels similar to those to MHg alone. In contrast, PCB and PCDD/PCDF mixtures did not suppress but augmented responses of splenocytes and peripheral blood lymphocytes to T cell mitogens. Overall, no interactive toxicity was observed with MHg/PCB/PCDD/PCDF mixtures on cytotoxicity and lymphocyte mitogenic responses. Therefore, MHg may pose a greater threat than organochlorines to the mammalian immune system.