BACKGROUNDComputed tomography (CT) screening has improved lung cancer survival, yet increasingly detected small lung lesions. The number of transthoracic lung biopsies (TTLB) for small nodules is thus expected to rise significantly.RESEARCH QUESTIONTo evaluate the diagnostic accuracy and safety of CT-guided TTLB for nodules ≤20 mm versus nodules >20mm.STUDY DESIGN AND METHODSData for CT-guided TTLBs from 474 consecutive patients were prospectively collected over a 3-year period (198 lesions ≤20 mm and 276 lesions >20 mm) in a teaching hospital and analysed in terms of diagnostic performance and complications.RESULTSThere were more conclusive biopsies in the >20 mm lesion group (n=236; 85.5%) than in ≤20 mm lesion group (n=140; 70.7%; p<0.001). The overall accuracy, sensitivity, specificity, and negative predictive value for diagnosing malignant lesions after first TTLB were 88.4%, 84%, 100%, and 70.1% for ≤20 mm lesions and 94.2%, 93%, 100%, and 74.6% for >20 mm lesions, respectively. Pneumothorax requiring drainage was significantly more common for ≤20 mm lesions, compared to TTLB of larger lesions (9.6% versus 4.3%; p=0.02). Prolonged hospital stay due to pneumothorax occurred in 27 (17.4%) TTLBs of ≤20 mm lesions and 15 (7%) TTLBs of >20mm lesions (p=0.002). There were no deaths. The only variable significantly associated with diagnostic failure in the ≤20mm lesion group was the radiologist's experience.INTERPRETATIONTTLBs for lesions ≤20 mm were associated with slightly lower diagnostic performance, whereas the higher rate of major complications was still inferior to that extrapolated from United States insurance databases.