Dystrophic cardiac calcinosis (DCC) is a frequent finding in DBA/2, C3H and BALB/c mice and its etiology is not known. Previous studies have speculated that myocardial necrosis is involved in the pathogenesis of DCC. In this study, cardiac necrosis was induced in DBA/2, C3H and C57BL/6 mice by freeze-thaw injury through the abdominal diaphragm. Four weeks after freeze-thawing, the mice were sacrificed and the hearts and diaphragms were examined. In response to injury, cardiac mineralization was present only in DBA/2 and C3H mice. The myocardium of C57BL/6 mice (control strain) healed by fibrosis without mineralization, the normal response of the myocardium to injury. Calcified diaphragms also were present at the site of freeze-thaw injury in DBA/2 and C3H mice, which is supportive evidence that a systemic abnormality is involved in the pathogenesis of DCC. The conclusion from this study is that the pathogenesis of DCC in DBA/2 and C3H mice is multifactorial and involves both myocardial necrosis and an abnormal response to injury.