Previous studies have demonstrated the protective effects of estrogen administration in models of cardiovascular disease. However, there is a discrepancy between these data and those of the recent clinical trials with hormone replacement therapy in menopausal women. One possible explanation for the divergent data is the addition of progestin to the hormone regimen in both the WHI and HERS trials. The aim of the current study was to examine the effects of a combination of 17-estradiol (E2; 20µg) and medroxyprogesterone acetate (MPA; 80µg) on infarct size in New Zealand white rabbits. The administration of E2, 30 minutes before induction of myocardial ischemia, significantly reduced infarct size as a percent of the area of risk (21.7 ± 5.2, P < 0.001) compared to vehicle (56.1 ± 3.4). However, when combined with MPA, E2 failed to elicit a reduction in infarct size (49.2 ± 5.2) and MPA alone had no effect (47.9 ±2.4). Treatment with E2 also reduced serum levels of cardiac troponin-I, immune complex deposition in myocardial tissue, activation of the complement system, and lipid peroxidation. All of these effects were reversed by MPA. The results suggest that MPA antagonizes the infarct-sparing effects of E2, possibly through modulation of the immune response after ischemia and reperfusion.