Purpose Electromagnetic navigation bronchoscopy is an emerging technique for diagnosing pulmonary lesions. However, limited data is available on its utility under a least-invasive without general anesthesia. This study aimed to evaluate the diagnostic performance and safety of sole ENB procedure under moderate sedation for the diagnosis of pulmonary lesions suspicious for lung cancer, and determine clinical factors associated with better diagnostic yield. Method We performed a retrospective analysis of consecutive patients who underwent sole ENB under moderate sedation for lung lesion biopsy between August 2016 and June 2021 at Seoul National University Bundang Hospital, a tertiary center in South Korea. Diagnostic yield of the ENB-guided biopsy, safety endpoints defined by incidence and severity of associated complications, and factors associated with higher diagnostic yield were evaluated. Result A total of 94 patients were evaluated. The final diagnostic yield of ENB was 81.5% excluding the 2 indeterminate cases. The diagnostic yield ranged from 79.8% to 81.9% assuming all indeterminate cases were false-negatives and true-negatives, respectively. Sensitivity and specificity for malignancy were 77.6% (ranged 75.6% to 77.6%) and 100%, respectively. Any-grade pneumothorax occurred in 4 of 94 (4.3%), and 2.1 (2/94%) developed pneumothorax requiring additional intervention. No respiratory failure events or deaths related to ENB were reported. By multivariable analyses, the presence of a class 2 bronchus sign was the only significant predictor for a higher diagnostic yield (OR = 4.83, 95% CI = 1.16 - 20.12). The diagnostic yield of ENB among those with class 2 bronchus sign was 89.8% (53/59). Conclusion Sole ENB under moderate sedation for the diagnosis of pulmonary lesions showed good diagnostic yield and safety profile, supporting the utility of ENB procedure in the least-invasive setting. For diagnosis of lesions with class 2 bronchus sign, sole ENB can possibly be superior to transthoracic needle aspiration.