Previous studies have suggested that (1) nitroglycerin causes vasodilatation by interacting with sulfhydryl groups in vascular smooth muscle, thereby activating guanylate cyclase and increasing the intracellular concentration of cyclic GMP, and (2) N-acetylcysteine, a source of sulfhydryl groups, potentiates the peripheral vasodilatory effect of nitroglycerin. This study was performed to explore the influence of N-acetylcysteine on nitroglycerin-induced coronary dilatation. In 18 patients (13 men and five women, 30 to 76 years old), coronary sinus blood flow (by thermodilution) was measured before and during intracoronary administration of nitroglycerin, 25 μg, both before and 5 min after a 15 min intravenous infusion of (1) 5% dextrose in water (n = 8, control) or (2) 100 mg/kg N-acetylcysteine (n = 10). Nitroglycerin caused no change in heart rate or systemic arterial pressure. In the control patients, coronary sinus blood flow behaved similarly during the two injections: it was 134 36 ml/min (mean ± SD) before and 183 + 50 ml/min during injection No. 1 (average increase, 49 25 ml/min; average percent increase, 38 + 21%); and it was 131 ± 34 ml/min before and 178 + 45 ml/min during injection No. 2 (average increase, 47 + 23 ml/min; average percent increase, 37 + 20%) (NS compared with injection 1). In the patients who received N-acetylcysteine, coronary sinus blood flow was 149 + 48 ml/min before and 191 + 54 ml/min during injection 1 (average increase, 42 + 15 ml/min; average percent increase, 30 + 12%) (NS compared with eight control values). After Nacetylcysteine, coronary sinus blood flow was similar before nitroglycerin (145 ± 44 ml/min), but it rose markedly with nitroglycerin (218 + 68 ml/min) (average increase, 73 + 35 ml/min; average percent increase, 50 20%) (p < .01 compared with the values obtained in the same patients during injection 1). Thus, N-acetylcysteine, a source of sulfhydryl groups, potentiates the coronary vasodilative effect of nitroglycerin.