Study objectives: Flexible bronchoscopy (FB) is an invasive procedure associated with patient discomfort and frequent nose pain. A simple sedation procedure that does not require the intervention of an anesthetist is of interest. The aim of this prospective, randomized, double-blind study was to assess efficiency of nitrous oxide inhalation on the reduction of FB-induced discomfort in adult patients. Design and settings: Two hundred six patients were randomized to receive either a prefixed equimolar nitrous oxide/oxygen mixture (N2O) or a prefixed equimolar nitrogen and oxygen mixture (control). The primary outcome was stress as assessed by pulse rate and systemic BP during the procedure. Secondary outcomes were self-assessed pain using a visual analog scale (VAS) and patient satisfaction based on a questionnaire. Adverse events were recorded. Results: A significant increase in BP was observed only in the control group (p = 0.003), while pulse rate values did not differ between the two groups. As assessed by the VAS, pain was lower in the N2O group as compared to placebo (p = 0.02). Nose pain and cough were also significantly reduced by N2O. Adverse events, mostly anxiety, were reported in 10 patients. Conclusion: These results indicate that equimolar N2O inhalation is efficient in reducing patient discomfort and may be an alternative to general anesthesia.