Ischemic heart disease (IHD) is the most common cause of death in most Western countries, but the therapies for IHD are lacking. We aimed to determine the potential of connective tissue growth factor (CTGF) antibody in protecting myocardium from long-term deleterious effects of myocardial infarction. Healthy 8-week old mice were subjected to myocardial infarction (MI) and at 1 week post-MI the animals were randomized for treatment with vehicle, metoprolol or CTGF monoclonal antibody. After six weeks of treatment, CTGF antibody treated animals showed significantly better left ventricular (LV) systolic function than the vehicle-treated animals. LV diastolic function or LV dimensions were not affected by treatments. Analysis of cardiac sections revealed no difference in infarct scar size between the experimental groups. However, RT-PCR analysis revealed a decrease in the expression levels of fibrosis-related genes in non-ischemic area in the hearts of CTGF antibody treated animals. In addition, cardiomyocyte size was significantly reduced in LV sections of CTGF antibody treated animals compared to vehicle-treated animals. This was accompanied with a significant decrease in B-type natriuretic peptide mRNA levels in the LV, whereas expression levels of atrial natriuretic peptide or beta-myosin heavy chain were similar in MI groups. There was also a slight decrease in mRNA levels of interleukin-6 and CTGF in the hearts of CTGF antibody treated animals. Treatments had no effect on mRNA levels of transforming growth factor-β1, tumor necrosis factor-α and vascular endothelial growth factor A following MI. In conclusion, CTGF antibody treatment attenuates LV hypertrophy and improves LV systolic function following MI. Blocking CTGF function by a specific antibody may be useful for prevention of adverse myocardial remodeling and heart failure.