Polychlorinated biphenyls (PCBs) are persistent food contaminants that can have adverse effects on the endocrine and nervous systems, including the pituitary. In the present study, we have investigated cell death in the AtT20 pituitary cell line after exposure to coplanar PCB 126 and non-coplanar PCB 153. In addition, co-exposure to the PCBs and another neurotoxic food contaminant, methylmercury (MeHg), was studied to test possible interactive effects. Our results show that mainly necrosis is induced after exposure to the selected toxicants. Simultaneous exposure to moderately toxic doses of PCBs and MeHg resulted in additive or slightly synergistic effects on the induction of cell death. Furthermore, our data suggest that both PCB congeners trigger cell death in AtT20 cells via activation of calcium regulated calpains and lysosomal cathepsins, possibly through disruption of mitochondrial function and intracellular calcium signaling. However, caspase-activity appears not to be critical for PCB induced cell death in these cells. Presence of reactive oxygen species (ROS) and protective effects of pre-treatment with antioxidants were only found after MeHg exposure, suggesting that oxidative stress plays a major role in MeHg but not PCB toxicity in this experimental model.