PURPOSE: To analyze the influence of multiple variables on the rate of pneumothorax and chest tube placement associated with transthoracic needle aspiration biopsy of the lung. MATERIALS AND METHODS: In 346 patients, 331 computed tomographically (CT) guided and 24 fluoroscopically guided lung biopsies were performed. Variables analyzed were lesion size, depth, and location; number of pleural passes; needle size; presence of emphysema; and training level of the person who performed the biopsy. RESULTS: Pneumothorax occurred at 144 (40.4%) of 356 biopsies, including 139 (42.0%) CT-guided and five (21%) fluoroscopically guided biopsies. Chest tube placement was needed in 25 (17.4%) of 144 cases of pneumothorax (7% of all biopsies). An increased rate of pneumothorax was correlated with smaller lesion size (P = .001) and presence of emphysema (P = .01). Patients with emphysema were three times as likely to require chest tube placement. The pneumothorax rate was 15% (16 of 105) if no aerated lung was traversed and approximately 50% if aerated lung was penetrated. Lesion location, needle size, number of pleural passes, and level of training were not correlated with pneumothorax rate. CONCLUSION: Smaller lesion size and emphysema are strongly correlated with occurrence of pneumothorax. Pneumothorax was more than three times less frequent if: no aerated lung was traversed. After pneumothorax, chest tube placements were related to the presence of emphysema.