Background: The endobronchial diagnosis of peripheral lung lesions suspected of lung cancer remains a challenge from a navigation as well as an adequate tissue sampling perspective. Cone-beam computed tomography (CBCT) guidance is a relatively new technology and allows for 3-dimensional imaging confirmation as well as navigation and biopsy guidance, but, also involves radiation. This study investigates how radiation exposure and diagnostic accuracy in the CBCT-guided navigation bronchoscopy evolves with increasing experience, and, with a specific tailoring of CBCT and fluoroscopic imaging protocols towards the procedure.Patients and Methods: In this observational clinical trial, all 238 consecutive patients undergoing a CBCT-guided navigation bronchoscopy from the start of our CBCT-guided navigation bronchoscopy program (December 2017) until June 2020 were included. Procedural dose characteristics and diagnostic accuracy are reported as a function of time.Results: Procedural radiation exposure as measured by the dose area product initially was 47.5?Gy·cm2 (effective dose: 14.3?mSv) and gradually reduced to 25.4?Gy·cm2 (5.8?mSv). The reduction in fluoroscopic dose area product was highest, from 19.0?Gy·cm2 (5.2?mSv) to 2.2?Gy·cm2 (0.37?mSv, 88% reduction), despite a significant increase of fluoroscopy time. The diagnostic accuracy of navigation bronchoscopy increased from 72% to 90%.Conclusion: A significant learning effect can be seen in the radiation safety and diagnostic accuracy of a CBCT-guided and augmented fluoroscopy–guided navigation bronchoscopy. With increasing experience and tailoring of imaging protocols to the procedure, the procedural accuracy improved, while the effective dose for patients and staff was reduced.