Overexpression of the leucine-rich, glioma-inactivated 1 (LGI1) gene in neuroblastoma cells inhibited proliferation and efficiently induced apoptosis. Cell clones stably transfected with LGI1 cDNA showed greater mortality during a period of serum starvation in comparison with control cells stably transfected with empty vector. This observation suggested hindrance of the PI3K/Akt pathway, a central transducer of survival stimuli elicited by serum growth factors. Treatment with inhibitors of PI3K significantly increased the death of control cells but substantially failed to influence LGI1 cell death, which was greatest independently of the presence of inhibitors. Blockage of the PI3K/Akt pathway in LGI1 cells was confirmed by the lack of serum-induced Akt phosphorylation, in contrast with the strong response of control cells. Instead, serum-induced phosphorylation of ERK1/2 was not impaired by the expression of LGI1. This study showed that overexpression of LGI1 caused neuroblastoma cell death by blocking activation of the PI3K/Akt pathway. Thus, the possibility of upregulating LGI1 expression may be a novel strategy in suppressing oncogenesis and metastasis sustained by excessive activation of the PI3K/Akt pathway.