PurposeC-arm cone-beam computed tomography-guided transthoracic lung core needle biopsy (CBCT-CNB) is a safe and accurate procedure for the evaluation of patients with pulmonary nodules. The purpose of our study was to evaluate the diagnostic performance, complication rates and effective radiation dose of CBCT-CNB with virtual guidance.Materials and MethodsWe retrospectively collected data regarding 375 CBCT-CNBs performed with virtual guidance (XperGuide—Philips Healthcare, Best, The Netherlands) from January 2010 to June 2015 on 355 patients (mean age, 68.1 years ± 11.8; age range, 31–88 years). Patients were divided into groups and compared based on the diagnostic failure and lesion size (15 mm cutoff). Diagnostic performance, complication rate and effective radiation dose were investigated. Variables influencing diagnostic performance and complications were assessed using Student’s T test and Pearson’s χ2 test.ResultsThe sensitivity, specificity, positive and negative predictive value and accuracy for patients subjected to CNBs were 96.8%, 100%, 100%, 100% and 97.2%, respectively. Considering risk factors for pneumothorax, no significant differences were found regarding patient and lesion characteristics. Perilesional hemorrhage occurred more frequently in older patients (p = 0.046) and in smaller lesions (p = 0.001). Hemoptysis was significantly more frequent in patients with perilesional hemorrhage (p = 0.01). Mean effective radiation dose in CBCT-CNB was 7.12 ± 8.78 mSv.ConclusionsCBCT-CNB combined with virtual guidance is a reliable and accurate technique that allows exact localization of pulmonary lesions, effective preprocedural planning and real-time fluoroscopy altogether.