Prolonged production of reactive oxygen species due to ischemia and reperfusion (I/R) is a potential cause of the pathologic remodeling that frequently precedes heart failure. We tested the ability of a potent dithiol antioxidant, bucillamine, to protect against long-term consequences of I/R injury in a murine model of myocardial infarction. After transiently occluding the left anterior descending coronary for 30 minutes, saline or bucillamine (10µg/g body weight) was injected intravenously as a bolus within the first 5 minutes of reperfusion. Anti-oxidant treatment continued with daily subcutaneous injections for four weeks. There were no differences in infarct sizes between bucillamine and saline treated animals. After four weeks of reperfusion, cardiac hypertrophy was decreased by bucillamine treatment (ventricular weight:body weight ratios: I/R + saline, 4.5±0.2 mg/g, versus I/R + bucillamine, 4.2±0.1 mg/g; mean±SE; P<0.05). Additionally, the hearts of bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32±3%, versus I/R + bucillamine, 41±4% (P<0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by ribonuclease protection assay that was consistent with pathologic cardiac hypertrophy and remodeling (increased ANP, -myosin heavy chain (MHC), skeletal -actin; decreased SERCA2a and -MHC/-MHC ratio). These changes in gene expression were significantly attenuated by bucillamine. Therefore, treatment with a dithiol antioxidant for four weeks after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathologic cardiac remodeling.