The contribution of increased inducible nitric oxide synthase (iNOS) activity to the development of left ventricular dysfunction after acute myocardial infarction (MI) was investigated New Zealand rabbits (n = 24) were randomly treated with either saline, S-methylisothiourea sulfate (SMT; selective iNOS inhibitor) or N-omega-nitro-L-arginine (NOLA; non-isoform selective NOS inhibitor). Left ventricular hemodynamics and myocardial blood flow were measured before coronary occlusion and on postoperative day 3 (POD 3). MI resulted in left ventricular dysfunction and increased myocardial iNOS activity. SMT and NOLA significantly inhibited iNOS activity; SMT, but not NOLA, significantly improved left ventricular maximum +dP/dt and decreased LVEDP; myocardial blood flow in the remote myocardium significantly increased after SMT. Induction of myocardial iNOS after MI on POD 3 contributes to the development of left ventricular dysfunction; modulation of iNOS activity by SMT improves left ventricular performance and may be beneficial after acute MI.