Background: The use of sedation during flexible bronchoscopy (FB) is undisputed; however, the combination of benzodiazepines and opiates, although reasonable, is suggested to cause hypoventilation, particularly in patients with pre-existing respiratory failure. Objectives: To assess respiratory function during FB. Methods: Transcutaneous PC O2 (PtcC O2), oxygen saturation, patients’ tolerance, time after FB until recovery and application of drug dosage were assessed in patients receiving either midazolam with alfentanil (n = 15) or midazolam alone (n = 15) for sedation for FB. Results: There were no differences in PtcC O2 values during FB between the two groups (all p > 0.05). However, PtcC O2 significantly increased over time in both groups (both p < 0.001; RM-ANOVA on ranks). Minimum oxygen saturation (SaO2) [89 (interquartile range 79.8/92.8) vs. 86 (interquartile range 82.3/87.8)%; p = 0.46] and the duration until recovery, i.e., achieving an ALDRETE score of ≧9 [30 (interquartile range 10/90) vs. 10 (interquartile range 10/105) min; p = 0.68] were comparable for monosedation and combined sedation, respectively. The total amount of midazolam [4.0 (interquartile range 4.0/4.0) vs. 2.0 (interquartile range 2.0/2.0) mg; p < 0.001] was lower in patients receiving combined sedation. Significantly lower scores for pain and asphyxia, and a clear tendency to less nausea and cough were reported by patients receiving combined sedation. Conclusions: Combined sedation during FB produced a comparable degree of desaturation and hypoventilation, and is associated with a comparable time to full recovery compared to monosedation in patients with pre-existing respiratory failure. Importantly, FB using combined sedation is better tolerated by patients despite only 50% midazolam consumption.