Several phenothiazines were found to provide significant protection against loss of tissue creatine phosphokinase caused by the calcium paradox. The concentration of phenothiazine required for protection lies within the range generally attributable to their calmodulin inhibition properties. Moreover, the order of effectiveness in protecting the calcium overloaded myocardium is consistent with their potency as calmodulin inhibitors (trifluoperazine greater than chloropromazine greater than promethazine). The most potent calmodulin inhibitor was shown to dramatically reduce the amount of creatine phosphokinase loss from calcium depleted hearts exposed to buffer containing calcium under anoxic conditions. On the other hand, the drug failed to alter the oxygen-dependent component of the calcium paradox. It also failed to prevent the proteolytic conversion of xanthine dehydrogenase to xanthine oxidase. The possibility that calmodulin activation promotes cellular damage by activating either directly or indirectly specific membrane cellular phospholipases is discussed. Also discussed is the hypothesis that oxygen-dependent damage may be linked to the generation of superoxide anion by the enzyme xanthine oxidase.