Ischemic heart disease represents a leading cause of death worldwide. Ischemia denotes an insufficient supply of oxygenated blood to the heart due to occlusion of the coronary vessels. Timely reperfusion, i.e., restoring blood flow to the ischemic part of the heart, limits ischemic damage. However, reperfusion itself induces injury to the heart. This phenomenon is referred as ischemia/reperfusion (I/R) injury. Osteopontin (OPN), also known as cytokine Eta-1, is a cell-secreted extracellular matrix protein. Expression of OPN increases in the heart in response to a variety of pathological conditions. Mice lacking OPN exhibit exaggerated left ventricular dilation in non-reperfused model of myocardial remodeling. Cardioprotective role of OPN has also been demonstrated in a mouse model of repetitive I/R injury for 7 days. The objective of this study was to examine the role of OPN in modulation of systolic and diastolic parameters of the heart following I/R injury in a time-dependent manner. For this study, wild type (WT) and OPN knockout (KO) mice aged ~4 months were subjected to cardiac ischemia by the ligation of left anterior descending coronary artery (LAD). Following 45 min of ischemia, the LAD was reperfused by snipping the ligature. Heart function was measured using echocardiography at baseline, 3, 7, 14, and 27 days following I/R injury. M-mode echocardiographic images were used to calculate the systolic parameters (% fractional shortening [%FS], % ejection fraction [%EF], and end-systolic volume [ESV]), while pulse wave Doppler images were used to calculate diastolic parameter (aortic ejection time; [AET]). Global cardiac function was evaluated using myocardial performance index (MPI; a Doppler-derived index which combines systolic and diastolic functions). At basal levels, most of the systolic and diastolic parameters remained unchanged between the two groups. I/R injury decreased %FS and EF in both groups vs the baseline values at 3, 7, 14 and 27 days post-I/R. However, the decrease in %FS and EF was significantly greater in KO-I/R vs WT-I/R group. ESV was significantly higher in WT mice 7 days post-I/R, and stayed higher 14 and 27 days post-I/R vs baseline. However, the increase in ESV was significantly greater in KO mice 3 day post-I/R, and remained higher vs WT-I/R during the time course. AET was lower in WT group 14 days post-I/R vs baseline. On the other hand, AET was significantly lower in KO group 3, 7, 14 and 27 days post-I/R vs WT-I/R. MPI was higher in WT group 7 days post-IR vs baseline. MPI decreased significantly in WT group 27 days vs 7 days post-I/R. In KO group, MPI was significantly higher than WT mice at baseline, and remained higher 3 and 27 day post-I/R vs WT-I/R. Thus, lack of OPN decreases systolic and diastolic functional parameters of the heart following I/R injury, suggesting a cardioprotective role of OPN in myocardial remodeling post-IR.