Polychlorinated biphenyls (PCBs) are a group of persistent and widespread environmental pollutants, and known to affect signaling molecules. Phospholipase A 2 (PLA 2 ) mediates cellular destructive processes as well as normal physiological responses in neuronal cells. In this study, we examined whether PLA 2 can be activated by PCBs in PC12 cells. Of the congeners tested, ortho-substituted PCBs were found to induce PLA 2 activation. PLA 2 activation by 2,2′,4,6-tetrachlorobiphenyl (TeCB), the most potent congener, was inhibited by bromoenol lactone (BEL), a calcium-independent PLA 2 (iPLA 2 ) inhibitor, and methyl arachidonyl fluorophosphonate (MAFP), a cytosolic PLA 2 and iPLA 2 inhibitor. In the case of Ca 2+ , although 2,2′,4,6-TeCB increased [Ca 2+ ] i in the presence of extracellular Ca 2+ , PLA 2 activation was not inhibited by EGTA and 1,2-bis (o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra (acetoxy-methyl) ester, an extracellular and an intracellular Ca 2+ chelator, respectively. On the other hand, 2,2′,4,6-TeCB-induced Ca 2+ increase was partially inhibited by BEL and MAFP. In addition, 2,2′,4,6-TeCB induced apoptotic cell death in these cells. Taken together, our results suggest that ortho-substituted PCBs might induce apoptosis through PLA 2 -mediated Ca 2+ influx, which provides a clue to understand the mechanism of neurotoxic effects of ortho-substituted PCBs.