Thapsigargin (THG), a selective inhibitor of endoplasmic reticulum (ER) Ca2+-ATPases, causes the rapid emptying of ER Ca2+; in some cell types, this is accompanied by apoptosis, whereas other cells maintain viability. In order to understand the molecular determinants of such a different behavior, we explored the role of oxygen versus nitrogen radicals, by analyzing the apoptogenic ability of THG in the presence of inhibitors of glutathione or nitric oxide (NO) synthesis, respectively. We observed that oxygen radicals play a sensitizing role whereas nitrogen radicals prevent THG-dependent apoptosis, showing that the apoptogenic effect of THG is redox sensitive.