This study examined the relationships between left ventricular (LV) regional function, regional myocardial blood flow (RMBF), and myocellular necrosis after sudden proximal occlusion of the left anterior descending coronary artery (LAD) in 36 awake, unsedated dogs. Net wall thickening during systole (NET) was used to assess regional LV function, was expressed as percent control, and was measured with chronically implanted ultrasonic crystals. RMBF was measured with 8- to 10-jun radioactive microspheres. In regions with a moderate degree of functional loss, NET fell to 35.3 ± 2.2% of control at 5 minutes when RMBF fell from 1.19 ± 0.08 to 0.86 ± 0.09 ml/g per min (P < 0.05). No significant change occurred in midwall or epicardial RMBF. The relationship between endocardial flow and NET was non-linear (r - 0.89, P < 0.0001). In these segments, subsequent changes in RMBF were unrelated to corresponding functional alterations through 24 hours. In segments with paradoxic systolic wall thinning RMBF fell in endocardial, midwall, and epicardial layers; endocardial ischemia was most severe (0.30 ± 0.0S ml/g per min). Segmental myocellular necrosis was most severe in the endocardial layer and correlated significantly with both RMBF and segmental function. Myocellular necrosis increased in severity as flow was reduced below 70–76% of normal. Thus, in this model of LV ischemia, (1) regional LV functional loss is most sensitive to reductions in endocardial RMBF; (2) subsequent increases in RMBF are largely unassociated with functional recovery; (3) transmural ischemia results in paradoxical systolic wall thinning.