The role of calcineurin (CN) pathway in the post-myocardial infarction (MI) heart remains unclear. We investigated effects of early and brief inhibition of CN pathway with cyclosporine A (CsA) after MI on both immediate and delayed changes in left ventricular (LV) morphology, haemodynamics, and cardiomyocyte performance. CsA/saline was administered for 4 days, starting 24 h after MI/sham surgery in the rat. MI resulted in CN overactivity, peaking on day 3, accompanied by significant intracellular Ca(2+) overload due to marked decrease of NCX function. On day 7 and in week 8, CN activity decreased and normalized, respectively. It was accompanied by normalization of Ca(2+) handling parameters (only SERCA function was moderately decreased). CsA abolished post-MI CN overactivity, protected against Ca(2+) overload on day 3 and slightly improved SERCA function on day 7. Moreover, CsA reduced hypertrophy on days 3 and 7 after MI, increased wall stress on day 7 and in week 8, and lowered ejection fraction, augmented LV dilation as well increased mortality in week 8. Our study demonstrates that blockade of brief post-MI CN overactivity with CsA has delayed detrimental effects: increased mortality and worse LV function. CsA prevented early cardiomyocyte hypertrophy, decreased wall thickness and thus increased the wall stress, the main stimulus for detrimental LV dilation. Furthermore, CsA treatment prevented early Ca(2+) overload related to decreased NCX function. Role of this early Ca(2+) overload is unclear; it might be an element of positive feedback loop amplifying CN activation in post-MI heart.