Cadmium (Cd) is a toxic metal capable of damaging brain. Studies have demonstrated that Cd can induce apoptosis in neuronal cells. The CD95/APO-1 (Fas)/Fas Ligand (FasL) signaling pathway is one of the primary apoptosis pathways, but the role and regulatory mechanism of this pathway in neuronal cells remain unclear. Here, we demonstrated the underlying mechanism of the Fas/FasL system involving the mitochondrial apoptotic pathway in neuronal cells. Primary rat cerebral cortical neurons and PC12 cells were exposed to Cd, which significantly activated expression of Fas, FasL, Fas-associated death domain (FADD) and cleaved caspase-8. However, expression of cleaved caspase-8 decreased at 20 µM Cd in primary cerebral cortical neurons. Importantly, Cd-induced apoptotic morphological changes and increase in the apoptosis rate were partially blocked by Z-IETD-FMK, which is a specific inhibitor of caspase-8. Cd-mediated increase of apoptosis rate was inhibited by anti-FasL antibody. Furthermore, our data revealed that Z-IETD-FMK also blocked increase of truncated BH3 interacting domain death agonist (tBID)/BID, decrease of the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associate X protein (Bax) ratio and mitochondrial membrane potential (MMP), release of cytochrome c, as well as cleavage of caspase-9/3 and poly (ADP-ribose) polymerase (PARP) induced by Cd. Taken together, our results demonstrate that the Fas/FasL-mediated mitochondrial apoptotic pathway plays an important role in Cd-induced neuronal apoptosis.