Flexible bronchoscopy (FBO) and non-invasive positive pressure ventilation (NIPPV) are largely applied in respiratory and general intensive care units. FBO plays a crucial role for the diagnosis of lung infiltrates of unknown origin and for the treatment of airways obstruction due to bronchial mucous plugging and hemoptysis in critical patients. NIPPV is the first-choice ventilatory strategy for acute respiratory failure (ARF) of different causes as it could be used as prevention or as alternative to the conventional mechanical ventilation (CMV) via endotracheal intubation (ETI). Some clinical scenarios represent contraindications for these techniques such as severe ARF in spontaneous breathing patients for FBO and accumulated tracheo-bronchial secretions in patients with depressed cough for NIPPV. In these contexts, the decision of performing ETI should carefully consider the risk of CMV-correlated complications. An increasing amount of published data suggested the use of FBO during NIPPV in ARF in order to avoid/reduce the need of ETI. Despite a strong rationale for the combined use of the two techniques, there is not still enough evidence for a large-scale application of this strategy in all different clinical scenarios. The majority of the available data are in favor of the "help" given by NIPPV to diagnostic FBO in high-risk spontaneously breathing patients with severe hypoxemia. Preliminary findings report the successful "help" given by early FBO to NIPPV in patients with hypoxemic-hypercapnic ARF who are likely to fail because of hypersecretion. Synergy of FBO and NIPPV application is emerging also to perform ETI in challenging situations, such as predicted difficult laringoscopy and NPPV failure in severely hypoxemic patients. This combined approach should be performed only in centers showing a wide experience with both NIPPV and FBO, where close monitoring and ETI facilities are promptly available.