Background Supine or prone positioning of the patient on the gantry table is the current standard of care for CT-guided lung biopsy; positioning biopsy side down was hypothesized to be associated with lower pneumothorax rate. Purpose To assess the effect of positioning patients biopsy side down during CT-guided lung biopsy on the incidence of pneumothorax, chest drain placement, and hemoptysis. Materials and Methods This retrospective study was performed between January 2013 and December 2016 in a tertiary referral oncology center. Patients undergoing CT-guided lung biopsy were either positioned in (a) the standard prone or supine position or (b) the lateral decubitus position with the biopsy side down. The relationship between patient position and pneumothorax, drain placement, and hemoptysis was assessed by using multivariable logistic regression models. Results A total of 373 consecutive patients (mean age ± standard deviation, 68 years ± 10), including 196 women and 177 men, were included in the study. Among these patients, 184 were positioned either prone or supine depending on the most direct path to the lesion and 189 were positioned biopsy side down. Pneumothorax occurred in 50 of 184 (27.2%) patients who were positioned either prone or supine and in 20 of 189 (10.6%) patients who were positioned biopsy side down (P < .001). Drain placement was required in 10 of 184 (5.4%) patients who were positioned either prone or supine and in eight of 189 (4.2%) patients who were positioned biopsy side down (P = .54). Hemoptysis occurred in 19 of 184 (10.3%) patients who were positioned prone or supine and in 10 of 189 (5.3%) patients who were positioned biopsy side down (P = .07). Prone or supine patient position (P = .001, odds ratio [OR] = 2.7 [95% confidence interval {CI}: 1.4, 4.9]), emphysema along the needle path (P = .02, OR = 2.1 [95% CI: 1.1, 4.0]), and lesion size (P = .02, OR = 1.0 [95% CI: 0.9, 1.0]) were independent risk factors for developing pneumothorax. Conclusion Positioning a patient biopsy side down for percutaneous CT-guided lung biopsy reduced the incidence of pneumothorax compared with the supine or prone position. © RSNA, 2019.