Increasing evidence has supported the general hypothesis that organochlorines (OC) can produce immunotoxic effects in marine mammals. One important innate defense mechanism is phagocytosis, the ability of cells to ingest extracellular macromolecules. The present study is aimed at characterizing the immunomodulatory potential of mixtures of OCs on phagocytosis compared to that of individual compounds in different species of marine mammals and mice, the traditional model to study mammalian immunotoxicity. The ability of peripheral blood neutrophils and monocytes to engulf fluorescent microspheres was evaluated using flow cytometry. The immunomodulatory effects of three non-coplanar polychlorinated biphenyl (PCB) congeners, 138, 153, 180, one coplanar PCB, 169, as well as 2,3,7,8-TCDD, and all possible mixtures (26) were tested upon in vitro exposure. All species were not equally sensitive to the adverse effects of OCs on either neutrophils or monocytes phagocytosis. With the exception of harbor seals, all mixtures that significantly modulated neutrophil or monocyte phagocytosis contained at least one non-coplanar PCB. Regression analysis revealed that the non-coplanar congeners, more than the coplanar congeners, explained the variability in phagocytosis. Dendrograms revealed that phylogeny could not predict immunotoxicity. The currently used toxic equivalency (TEQ) approach and the traditional mouse model both failed to predict experimentally induced immunomodulatory effects in marine mammals tested, leading us to question the reliability of both TEQs and mouse model in risk assessment of OC mixtures. Testing the relative sensitivity to immunomodulatory effects of contaminants and contaminant mixtures between different species of marine mammals may have important implications for risk assessment as well as conservation and management strategies.