RationaleStrict adherence to procedural protocols and diagnostic definitions is critical to understand the efficacy of new technologies. Electromagnetic navigational bronchoscopy (ENB) for lung nodule biopsy has been utilized for decades without a solid understanding of its efficacy but offers the opportunity for simultaneous tissue acquisition via electromagnetic navigation transthoracic biopsy (EMN-TTNA), and staging via endobronchial ultrasound (EBUS).ObjectiveTo evaluate the diagnostic yield of EBUS, ENB, and EMN-TTNA during a single procedure using a strict a priori definition of diagnostic yield, with central pathology adjudication.MethodsParticipants with pulmonary nodules (<3cm, without radiographically enlarged mediastinal lymph nodes) were prospectively enrolled and underwent a staged procedure with a same-day CT, EBUS, ENB, and EMN-TTNA. A study was diagnostic if an independent pathology core lab confirmed malignancy or a definitive benign finding. The primary endpoint was the diagnostic yield of the CT+EBUS+ENB+EMN-TTNA.Main results160 participants at 8 centers with a mean nodule size of 18 ±6mm were enrolled. The diagnostic yield of the combined procedure was 59% (94/160, 95%CI 51-66%). Nodule regression was found on same-day CT in 2.5% (4/160, 95%CI 0.69-6.3%) and EBUS confirmed malignancy in 7.1% (11/156, 95%CI 3.6-12%) of cases. The yield of ENB alone was 49% (74/150, 95%CI 41-58%), EMN-TTNA alone 27% (8/30, 95%CI 12-46%), and ENB+EMN-TTNA was 53% (79/150, 95%CI 44-61%). Complications included a pneumothorax rate of 10% and a 2% bleeding rate.ConclusionsThe diagnostic yield for ENB is 49%, which increases to 59% with the addition of same-day CT, EBUS, and EMN-TTNA, lower than prior reports in the literature. Clinical trial registration available at www.Clinicaltrialsgov, ID: NCT03338049.