Histone deacetylase (HDAC) determines the acetylation status of histones, and thereby controls the regulation of gene expression. HDAC inhibitors have been shown to inhibit the cardiomyocyte growth in vitro and in vivo. We assessed whether HDAC inhibitors exert beneficial effect on the remodeling heart in infarcted rats. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats were randomized to either vehicle, HDAC inhibitors valproic acid and tributyrin, an agonist of HDAC theophylline, or a combination of valproic acid and theophylline or tributyrin and theophylline for 4 weeks. Significant ventricular hypertrophy was detected by increased myocyte size at the border zone isolated by enzymatic dissociation after infarction. Treatment with either valproic acid or tributyrin significantly attenuated cardiomyocyte hypertrophy and collagen formation at the remote region and at the border zone with a similar potency, as compared with the vehicle-treated group. Left ventricular shortening fraction was significantly higher in the valproic acid- or tributyrin-treated groups compared with the vehicle-treated group. Increased synthesis of atrial natriuretic peptide mRNA after infarction was confirmed by reverse transcription-polymerase chain reaction, consistent with the results of immunohistochemistry and Western blot for acetyl histone H4. The beneficial effects of valproic acid and tributyrin were abolished by administering theophylline, implicating HDAC as the relevant target. Inhibition of HDAC by either valproic acid or tributyrin administration can attenuate ventricular remodeling after infarction. This might provide a worthwhile therapeutic target.