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We have recently shown that melatonin antagonizes damage‐induced apoptosis by interaction with the MT‐1/MT‐2 plasma membrane receptors. Here, we show that melatonin interferes with the intrinsic pathway of apoptosis at the mitochondrial level. In response to an apoptogenic stimulus, melatonin allows mitochondrial translocation of the pro‐apoptotic protein Bax, but it impairs its activation/dimerization The downstream apoptotic events, i.e. cytochrome c release, caspase 9 and 3 activation and nuclear vesiculation are equally impaired, indicating that melatonin interferes with Bax activation within mitochondria. Interestingly, we found that melatonin induces a strong re‐localization of Bcl‐2, the main Bax antagonist to mitochondria, suggesting that Bax activation may in fact be antagonized by Bcl‐2 at the mitochondrial level. Indeed, we inhibit the melatonin anti‐apoptotic effect (i) by silencing Bcl‐2 with small …