Carbon monoxide (CO) is known to protect myocardial and vascular cells against injuries due to ischemia-reperfusion or inflammation. We showed that a Ca2+-dependent protease calpain promotes necrotic cell death of cardiomyocyte-derived H9c2 cells due to hypoxia through alpha-fodrin proteolysis. Here, we show that ischemia induces necrotic cell death, which is inhibited by either CO, extracellular Ca2+ deprivation or L-type Ca2+ channel blockers. A whole cell patch-clamp experiment supports that CO inhibits L-type Ca2+ channel mediated influx of Ca2+ and the ischemic death of H9c2 cells. (c) 2005 Published by Elsevier Inc.