Inflammation induces cardiac fibrosis and hypertrophy in multiple cardiovascular diseases, contributing to cardiac dysfunction. We tested the hypothesis that pentoxifylline (PTX), a phosphodiesterase inhibitor with anti-inflammatory property, would attenuate cardiac fibrosis and hypertrophy, and prevent cardiac dysfunction in angiotensin (ANG) II-induced hypertensive rats. Sprague-Dawley rats were divided into control and ANG II-infused groups treated with or without PTX for 2 weeks. PTX had no effect on ANG II-induced hypertension, but significantly attenuated cardiac fibrosis and hypertrophy, and ameliorated cardiac dysfunction in ANG II-induced hypertensive rats. In addition, ANG II-induced increase in circulating and cardiac proinflammatory cytokines were attenuated by PTX, which reduced cardiac nuclear factor-kappa B activity. Furthermore, PTX decreased cardiac expression of genetic markers important for fibrosis, hypertrophy, and endothelial dysfunction, and reduced migration and infiltration of macrophages. In contrast, PTX had no effects on the above parameters in control rats. The findings suggest that PTX ameliorates cardiac fibrosis, pathological hypertrophy, and cardiac dysfunction by suppressing inflammatory responses in angiotensin II-induced hypertension, and that these benefits were independent of the blood pressure lowering effect. The PTX by its anti-inflammatory property may be a potential therapeutic option for the prevention of cardiac remodeling and dysfunction in ANG II-induced hypertension.