Although direct ventricular tachycardia (VT) surgery has been shown to be effective for treatment of inferior myocardial infarction (MI), the differences in the arrhythmia substrates compared to anterior MI have not been systematically delineated. We sought to compare operative procedures and VT substrates between anterior and inferior MI locations. Computerized mapping was performed in 30 patients with a 128-electrode system using epicardial sock and transatrial left ventricular endocardial balloon arrays, followed by combined endocardial resection and cryoablation. At surgery, there were 51 and 34 different VTs in 18 patients with anterior MI and 12 patients with inferior MI, respectively. The proportion of aneurysms was lower in inferior MI (25% vs 78%, P = 0.008). Total activation times accounted for 65% +/- 23% and 50% +/- 22% of the VT cycle length in anterior and inferior infarcts, respectively (P = 0.005). Complete superficial reentry was identified in 12 VTs related to anterior infarcts and in only two VTs associated with inferior infarction (P = 0.038). Involvement of papillary muscles occurred in two patients with inferior MI. Patients with inferior infarcts received more cryolesions and required epicardial cryolesions or mitral valve replacement more frequently, and their operative mortality was greater (2/12 vs 0/18). Noninducibility rate (89.3%) and 2-year survival (76% +/- 8%) did not differ according to infarct location. VT associated with inferior MI can be ablated successfully; however, the substrate is more complex, with frequent participation of intramural layers rendering the ablative procedure more difficult.