Endothelial injury is a central feature of vascular disease induced by cigarette smoking and may act as a precursor for future atherosclerosis. Using forearm occlusion plethysmography, we studied the vascular responses to methacholine (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator) infused into the brachial artery of 35 long-term cigarette smokers and 16 nonsmoking subjects. NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide production, was used to inhibit synthesis of nitric oxide in the endothelium. The reactive hyperemic response at peak and during recovery to the temporary interruption of forearm blood flow was also compared between groups. Smokers had elevated carboxyhemoglobin levels compared with nonsmokers (5.1 +/- 2.1% vs 0.8 +/- 0.4%; p < 0.001). No differences were found in the peak or late hyperemic responses between groups. In smokers, the incremental infusions of methacholine and sodium nitroprusside increased forearm blood flow from 3.6 +/- 1.2 to 12.9 +/- 9.0 ml.min-1 x 100 ml-1 and from 4.0 +/- 1.5 to 9.3 +/- 4.0 ml.min-1 x 100 ml-1, respectively, compared with 3.2 +/- 1.0 to 13.5 +/- 5.6 ml.min-1 x 100 mL-1 and from 2.9 +/- 0.7 to 8.6 +/- 4.2 ml.min-1 x 100 ml-1 in nonsmoking subjects (p = NS). L-NMMA (4 mumol/min for 5 minutes) significantly reduced forearm blood flow in both smokers and nonsmokers from 4.1 +/- 1.4 to 3.4 +/- 1.2 ml.min-1 x 100 ml-1 and 3.8 +/- 0.7 to 2.3 +/- 0.5 mL.min-1 x 100 ml-1, respectively (p < 0.01 for both); and the decrement in forearm blood flow in nonsmokers was significantly greater than that recorded in smoking subjects (p < 0.05). In this study, long-term cigarette smokers exhibited an impairment in basal, but not stimulated, nitric oxide-mediated vasodilation.