The effects of organochlorines (OC) on the immune systems of marine mammals and humans are poorly understood. One important innate immune function of peripheral blood neutrophils and monocytes is the respiratory burst, which generates reactive oxygen species (ROS) used to kill engulfed microorganisms. The present study characterized the immunomodulatory potential for mixtures of OCs, compared to that of individual OCs, on the respiratory burst in several marine mammals, humans, and B6C3F1 mice. The effects of three non-coplanar polychlorinated biphenyls (PCBs) (138, 153, 180), one coplanar PCB (169), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and all possible mixtures were tested upon in vitro exposure for 1 h, and their effects on the generation of a respiratory burst were measured by flow cytometry. The final concentration for each congener, alone or in a mixture, was 5 ppm for PCBs and 0.05 ppb for TCDD. Both significant enhancement and suppression of the respiratory burst occurred in all species tested, but the pattern was different between species and cell types (neutrophils vs. monocytes). Both coplanar and non-coplanar OCs were involved in the modulation of the respiratory burst. Regression analysis was not able to elucidate which OCs were involved in modulating the responses, highlighting the difficulty of developing models to predict the immunotoxic effects attributed to OC mixtures. The traditional mouse model and toxic equivalency (TEQ) approach both failed to consistently predict the toxicity of OCs in all species tested, questioning their applicability in the risk assessment process for all species. Elucidating the relative sensitivities to the immunomodulatory effects of OC mixtures between different species may have important implications for risk assessment as well as conservation and management strategies.