To determine whether the inhibition of nitric oxide (NO) synthesis attenuates thermally induced obstruction, we had 10 asthmatic volunteers perform isocapnic hyperventilation with frigid air after inhaling 1 mg of N G-monomethyl-l-arginine (l-NMMA) or isotonic saline in a blinded fashion. The challenges were identical in all respects, and there were no differences in baseline lung function [1-s forced expiratory volume (FEV1); saline 2.8 ± 0.3 liters, l-NMMA 2.9 ± 0.3 liters; P = 0.41] or prechallenge fractional concentration of nitric oxide in the exhaled air (FeNO) [saline 23 ± 6 parts/billion (ppb),l-NMMA 18 ± 4 ppb; P = 0.51]. Neither treatment had any impact on the FEV1, pulse, or blood pressure. After l-NMMA, FeNO fell significantly ( P < 0.0001), the stimulus-response curves shifted to the right, and the minute ventilation required to reduce the FEV1 20% rose 53.5% over control ( P = 0.02). The results of this study demonstrate that NO generated from the airways of asthmatic individuals may play an important role in the pathogenesis of thermally induced asthma.