Introduction Our aim was to evaluate the diagnostic and safety performance of shape-sensing robotic-assisted bronchoscopy (ssRAB) with cone beam CT (CBCT) for the biopsy of pulmonary nodules. Additional analysis was performed to assess outcomes for small nodules and those close to the fissure, pleura or mediastinum. Methods This single arm, multicentre prospective study enrolled 200 subjects with suspicious pulmonary nodules. Each subject underwent a ssRAB procedure with CBCT and was subsequently followed up. The primary outcome was tool-in-lesion (TIL) confirmed with CBCT. Further endpoints included diagnostic outcomes and rate of adverse events. Results Of 200 subjects recruited, 198 subjects had a successful biopsy (whereby lesion was reached and sample was taken) and 97% completed the required follow-up. The median size of the nodules was 13 mm; 26.8% (60/224) have a positive bronchus sign and 181 (80.8%) were located in the outer two-thirds of the lung. TIL was obtained in 99.0% (198/200). The strict diagnostic yield was 85% (170/200) with diagnostic accuracy of 92.0% (184/200) and sensitivity for malignancy of 95.5% (147/154). Diagnostic accuracy for nodules under 20 mm size, within 5 mm from a critical structure (eg, heart, aorta or main pulmonary artery) or from the pleura was 88.2% (172/195), 100% (11/11) and 93.3% (56/60), respectively. There were four (2%) serious procedure-related adverse events, with one patient (0.5%) suffering a pneumothorax. Conclusion ssRAB with CBCT can effectively reach and biopsy small pulmonary nodules, including perifissural, peripleural and paramediastinal lesions with a strong safety profile. Trial registration number NCT05867953 .