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Purpose: To evaluate the safety and diagnostic performance of pulmonary nodule biopsies using cone-beam computed tomography (CBCT) guidance compared with conventional CT (CCT) guidance. Material and methods: Patients who had pulmonary nodules and underwent a transthoracic needle biopsy at the interventional unit from January 1, 2013 to June 30, 2018 were enrolled. CBCT with XperGuide software was used to biopsy 100 nodules, and CCT guidance was used to biopsy 266 nodules. The two techniques were compared in terms of radiation exposure, complications, and diagnostic accuracy. The p values of less than 0.05 were considered statistically significant. Results: The characteristics of the nodules were similar between CBCT and CCT guidance. The median radiation doses were not significantly different between the two groups (5.6 mGy vs. 5.4 mGy; p = 0.78). All minor, major, and overall complications were insignificant (25% vs. 24.4%, 3% vs. 4.9% and 28% vs. 29.3%, respectively). Although CBCT guidance showed higher sensitivity and accuracy than CCT guidance (93.3% vs. 84.1% and 95.0% vs. 89.9%), both techniques had similar specificity (100% vs. 100%) in the diagnosis of malignancy. Conclusions: CBCT guidance in pulmonary nodule biopsy provided higher diagnostic sensitivity and accuracy than CCT guidance. However, the complication rates and effective radiation doses did not differ between both techniques.