Recent reports, including from our laboratories, indicate that hyperhomocysteinemia (Hhe) is an independent risk factor for cardiac dysfunction and clinical heart failure. Mast cell accumulation is a prominent feature in our model of Hhe-induced cardiac dysfunction. Since mast cell-derived mediators can potentially attenuate cardiac remodeling, we investigated the protective role of mast cells in Hhe-induced cardiac remodeling using a mast cell deficient rat model, which in our recent report did not demonstrate any adverse effect on cardiac function at younger age (6 months) compared to mast cell competent controls. Methods: Mast cell deficient (Ws/Ws) rats and mast cell competent (+/+) littermate controls (3 months of age) were treated with Hhe-inducing diet for 10 weeks. Cardiac remodeling was assessed structurally utilizing histomorphometric methods, and functionally using the isolated Langendorff-perfused heart preparation. Results: The Hhe-inducing diet caused similar elevation of plasma homocysteine level in the two groups. Compared to Hhe +/+ rats, the Hhe Ws/Ws rats demonstrated strikingly exacerbated adverse cardiac remodeling and myocardial fibrosis. Cardiac function measurement showed worsened diastolic function in the Hhe Ws/Ws rats, compared to Hhe +/+ rats. Conclusions: The absence of mast cells strikingly exacerbates Hhe-induced adverse cardiac remodeling and diastolic dysfunction. These findings indicate a potential dual, rather than solely deleterious role for mast cells in cardiac injury.