Electromagnetic navigation bronchoscopy (ENB) and shape-sensing robotic-assisted bronchoscopy (ssRAB) are minimally invasive technologies for the diagnosis of pulmonary nodules. Cone-beam computed tomography (CBCT) has shown to increase diagnostic yield by allowing real-time confirmation of position of lesion and biopsy tool. There is a lack of comparative studies of such platforms using CBCT guidance to overcome computed tomography to body divergence. The aim of this study was to compare the diagnostic yield of ENB- and ssRAB-guided CBCT for biopsy of pulmonary nodules. We conducted a retrospective comparative study of consecutive patients undergoing ENB-CBCT and ssRAB-CBCT. Navigational success was defined as biopsy tool within lesion confirmed during CBCT. Diagnostic yield was assessed using two methods: (I) presence of malignancy or benign histological findings that lead to a specific diagnosis at the time of bronchoscopy, and (II) longitudinal follow-up of patients with nonspecific benign finding during bronchoscopy. ENB-CBCT was used to biopsy 97 nodules and ssRAB-CBCT was used to biopsy 111 nodules. Median size of the lesion for the ENB-CBCT group was 16.5 mm [interquartile range (IQR), 12-22 mm] as compared to 12 mm (IQR, 9-16 mm) in the ssRAB-CBCT group (P<0.001). Navigational success was 70.1% in ENB-CBCT arm as compared to 83% in ssRAB-CBCT arm respectively (P=0.03). Diagnostic yield was 66% for ENB-CBCT and 89.2% for ssRAB-CBCT (P<0.001) following bronchoscopy; 79.4% for ENB-CBCT and 95.4% for ssRAB-CBCT (P<0.001) with longitudinal follow-up data respectively. Following multivariate regression analysis adjusting for the size of the lesion, distance from the pleura, presence of bronchus sign, number of CBCT spins, and number of nodules, the odds ratio for the diagnostic yield was 4.72 [95% confidence interval (CI): 2.05-10.85; P<0.001] in the ssRAB-CBCT group as compared with ENB-CBCT. The overall rate of adverse events was similar in both groups (P=0.77). ssRAB-CBCT showed increased navigational success and diagnostic yield as compared to ENB-CBCT for pulmonary nodule biopsies.