Amyloid precursor protein (APP), the precursor of Aβ, has been shown to function as a cell surface receptor that mediates neuronal cell death by anti‐APP antibody. The c‐Jun N‐terminal kinase (JNK) can mediate various neurotoxic signals, including Aβ neurotoxicity. However, the relationship of APP‐mediated neurotoxicity to JNK is not clear, partly because APP cytotoxicity is Aβ independent. Here we examined whether JNK is involved in APP‐mediated neuronal cell death and found that: (i) neuronal cell death by antibody‐bound APP was inhibited by dominant‐negative JNK, JIP‐1b and SP600125, the specific inhibitor of JNK, but not by SB203580 or PD98059; (ii) constitutively active (ca) JNK caused neuronal cell death and (iii) the pharmacological profile of caJNK‐mediated cell death closely coincided with that of APP‐mediated cell death. Pertussis toxin (PTX) suppressed APP‐mediated cell death but not caJNK‐induced cell death, which was suppressed by Humanin, a newly identified neuroprotective factor which inhibits APP‐mediated cytotoxicity. In the presence of PTX, the PTX‐resistant mutant of Gα_o, but not that of Gα_i, recovered the cytotoxic action of APP. These findings demonstrate that JNK is involved in APP‐mediated neuronal cell death as a downstream signal transducer of G_o.