Progressive fibrosis is a pathological hallmark of many chronic diseases responsible for organ failure. The dynamic fibrogenic process is known to be regulated by multiple soluble mediators that may be therapeutically intervened. The failing hamster heart exhibits marked fibrosis and increased expression of secreted Frizzled-related protein 2 (sFRP2) amenable to reversal by mesenchymal stem cell (MSC) therapy. Given the previous demonstration that sFRP2-null mice subjected to myocardial infarction exhibited reduced fibrosis and improved function, we tested whether antibody-based sFRP2 blockade might counteract the fibrogenic pathway and repair cardiac injury. Cardiomyopathic hamsters were injected intraperitoneally twice a week each with 20 μg of sFRP2 antibody. Echocardiography, histology and biochemical analyses were performed after one month. sFRP2 antibody increased left ventricular ejection fraction from 40 ± 1.2% to 49 ± 6.5%, whereas saline and IgG control exhibited a further decline to 37 ± 0.9% and 31 ± 3.2%, respectively. Functional improvement is associated with a ~50% reduction in myocardial fibrosis, ~65% decrease in apoptosis and ~75% increase in wall thickness. Consistent with attenuated fibrosis, both MSC therapy and sFRP2 antibody administration significantly increased the activity of myocardial matrix metalloproteinase-2. Gene expression analysis of the hamster heart and cultured fibroblasts identified Axin2 as a downstream target, the expression of which was activated by sFRP2 but inhibited by therapeutic intervention. sFRP2 blockade also increased myocardial levels of VEGF and HGF along with increased angiogenesis. These findings highlight the pathogenic effect of dysregulated sFRP2, which may be specifically targeted for anti-fibrotic therapy.