Contaminant-induced immunosuppression by organochlorines, particularly polychlorinated biphenyls (PCBs), has been suspected as a co-factor in the deaths of thousands of cetaceans and pinnipeds. The immunotoxic effects of PCBs on marine mammals warrant further investigation, since the immune system plays a central role in the health and disease management of the animals. The present study is aimed at characterizing immunomodulatory potential for mixtures of organochlorines compared to that of individual compounds, and compares the relative sensitivity of different species of marine mammals and mice. Immune assays evaluated included: (i) lymphocyte proliferation, the ability of lymphocytes to divide upon stimulation with a mitogen; (ii) phagocytosis, the ability of phagocytic cells to engulf fluorescent microspheres; and (iii) natural killer (NK) cell activity, the ability of NK cells to lyse tumor and virus-infected cells. Individual PCB congeners, PCB 138, PCB 153, PCB 169, and PCB 180, as well as 2,3,7,8-TCDD and all 26 possible combinations were tested. Using mitogen-induced lymphocyte proliferation with the T-cell mitogen, ConA, 20 mixtures significantly reduced proliferation in mice. Two mixtures significantly reduced killer whale proliferation, while four mixtures significantly increased Commerson's dolphin proliferation. No mixtures affected beluga proliferation. Using the B-cell mitogen, LPS, 13 mixtures significantly reduced mouse proliferation. Two mixtures significantly decreased beluga monocyte phagocytosis while four mixtures significantly increased northern fur seal neutrophil phagocytosis. No mixtures affected mouse phagocytosis. Two mixtures in beluga whales significantly increased NK activity, while no mixtures affected mouse NK activity. Our results suggest that the widely used mouse model may not accurately represent the risks associated with exposure to mixtures of organochlorines in all species. Our results suggest both synergistic and antagonistic interactions between congeners. Testing the relative sensitivity to immunomodulatory effects of contaminants and contaminant mixtures between different species of marine mammals will have important implications for risk assessment as well as conservation and management strategies.