Rationale: Nitric oxide bioactivity, mediated through the formation of S-nitrosothiols (SNOs), has a significant effect on bronchomotor tone. S-nitrosogluathione (GSNO) is an endogenous bronchodilator that is decreased in children with asthmatic respiratory failure and in adults with asthma undergoing segmental airway challenge. Recently we showed that S-nitrosoglutathione reductase (GSNOR) regulates endogenous SNOs. Mice with genetic deletion of GSNOR are protected from airway hyperresponsivity in an allergic asthma model. Objective: We hypothesized that GSNOR is increased in human asthma and correlates with lung SNO content and airway reactivity. Methods: We recruited 36 subjects with mild asthma with FEV1 (88.5±2.3% predicted) and 34 healthy control subjects with FEV1 (100.7±2.5% predicted). BAL was performed in all subjects. Cell counts, differentials, GSNOR activity and SNO levels were determined in BAL. Results: SNO content was decreased in asthmatic BAL compared to control BAL and correlated inversely with GSNOR expression in BAL cell lysates. Furthermore, GSNOR activity measured from BAL samples was significantly increased in asthmatics compared to controls and correlated inversely with methacholine PC20. Conclusions: These findings suggest that GSNOR is an important regulator of airway SNO content and airways hyperresponsiveness in human asthma.