Cardiac rupture can be fatal after myocardial infarction (MI). Experiments in animals revealed gender differences in the rupture rate; however, patient data are controversial. We found that female mice given supplemental testosterone had a significantly higher rupture rate than placebo within the first week post-MI, while castration in males significantly reduced rupture. We hypothesized that testosterone may have adverse effects on remodeling post-MI, exaggerating the inflammatory response and increasing cardiac rupture, whereas estrogen may confer cardioprotection, attenuating early remodeling and reducing rupture rate. We studied the effect of gender and hormone manipulation, focusing on morphological and histological changes during early remodeling post-MI and how these events could affect cardiac function. Four-week-old male and female C57BL/6J mice were used. Females were randomly divided into: 1) shamovariectomy+ placebo (s-ovx+P), 2) s-ovx+testosterone (T), 3) ovx+P, and 4) ovx+T; and males: 1) sham-castration+P (s-cas+P), 2) s-cas+17-estradiol (E), 3) cas+P, and 4) cas+E. Six weeks after gonadectomy and hormone manipulation, MI was induced. Mice were randomly killed 1, 2, 4, 7, and 14 days after MI. The left ventricle (LV) was weighed and sectioned to evaluate MI size, infarct expansion index (IEI), and neutrophil infiltration. Transthoracic echocardiography was performed in conscious mice in the 14-day-group before organ harvest. Females that received testosterone and non-castrated males had a significantly higher cardiac rupture rate and IEI than controls, accompanied by enhanced neutrophil infiltration and pronounced deterioration of cardiac function and LV dilatation. Ovariectomy in females and estrogen supplementation in males did not confer any significant benefit in cardiac rupture, IEI, or neutrophil infiltration. We concluded that in mice high levels of testosterone enhance acute myocardial inflammation, adversely affecting myocardial healing and early remodeling, as indicated by increased cardiac rupture and possibly causing deterioration of the cardiac function after MI, while estrogen does not seem to have a significant protective effect in the acute phase post-MI.