The question of vascular tolerance was examined in 154 patients with acute myocardial infarction (64 anterior, 90 inferior) who were treated with prolonged low dose intravenous nitroglycerin in a recent randomized placebo-controlled study. The dose of nitroglycerin was carefully titrated to decrease mean Mood pressure by 10% in normotensive patients and 30% in hypertensive (blood pressure > 140/90 mm Hg) patients, but not <80 mm Hg. Tolerance was defined as the need to increase the dose to maintain this hemodynamic effect. It was labelled “true” H chest pain was absent and “apparent” if chest pain was present. Group analysis of dose, pain scores, hemodynamic, 2-dimensional echocardiographic and clinical parameters monitored serially before and after therapy indicated benefit with nitroglycerin over placebo despite equalling of blood pressures after 10 hours. Reversal of blood pressures and volumes after discontinuing nitroglycerin suggested lack of significant tolerance. However, detailed individual analysis suggested significant hemodynamic tolerance in 37 patients (24%), both in the true tolerance (12%) and apparent tolerance (12%) subgroups. Tolerance appeared early, requiring the dose to be increased by 30 ± 39 μg/min within 11 ± 9 hours. The dose was greater (p < 0.001) in the tolerance than in the no tolerance subgroup, both before (60 vs 27 μg/min) and after (90 vs 38 μg/min) 10 hours. Tolerance blunted the beneficial effect on infarct size, but positive effects on function, topography and complications persisted.