The cyclooxygenase (COX)-2 inhibitors celecoxib and rofecoxib were studied for their effects on neonatal rat cardiac myocytes as a possible model for the adverse cardiovascular effects that this class of compounds have shown in their clinical use. Celecoxib, but not rofecoxib, as measured by lactate dehydrogenase release was toxic to myocytes in the low micromolar concentration range. This toxicity shown by celecoxib was also associated with a high degree of myofibrillar disruption similar to that caused by doxorubicin. As measured by induction of caspase-3/7 activity and by changes in nuclear morphology, neither celecoxib nor rofecoxib strongly induced apoptosis in myocytes. The stable prostacyclin analog iloprost was unable to reduce celecoxib-induced damage, which suggested that celecoxib exerted its cytotoxicity through prostacyclin-independent pathways. Celecoxib treatment did not increase intracellular oxidation of 2′,7′-dichlorofluorescin in myocytes, which suggested that its cytotoxicity was not due to reactive oxygen species generation. The evidence supports the conclusion that celecoxib exerts its cytotoxicity towards myocytes through COX-2-independent mediated pathways.