Organochlorines (OC) are lipophilic and stable, and therefore accumulate in tissues of top predators, such as marine mammals. While the immunomodulatory effects of individual OC have been studied in lab animals, their effects in other species (such as marine mammals) and the possible interactions between chemicals in mixtures are not well understood. This study investigated the immunomodulatory effects of four polychlorinated biphenyls (PCB, IUPAC numbers 138, 153, 169, and 180), as well as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), individually and in mixtures, in marine mammals and mice. Mitogen-induced B lymphocyte proliferation was mostly modulated by non-coplanar PCBs, for which general mechanisms underlying toxicity are poorly understood. Simple additive effects of OC in mixtures were found only in mice, while both synergistic and antagonistic interactions between OC were found in marine mammals. The toxic equivalency (TEQ) approach, which is currently used to assess the dioxin-like toxicity of OC mixtures, failed to predict immunotoxicity in mice and marine mammals, likely due to the complexity of interactions between OC and effects via dioxin-independent pathways. The commonly used mouse model failed to predict the immunotoxicity due to OC in the marine mammals tested. In addition, clustering data suggested that phylogeny might not help predict the toxicity of OC. Lymphoproliferative response was modulated in most species tested suggesting the possibility of increased susceptibility to infectious diseases in these animals. These findings may be helpful in more accurately characterizing the immunotoxic potential of OC in different target species and help in more relevant risk assessment.