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The risk factors and outcomes of critically ill patients with iatrogenic pneumothorax (IP) have not been studied in a large unselected intensive care unit (ICU) population.The authors studied a prospective cohort of adults admitted for more than 24 h. Data were collected at ICU admission and daily by senior physicians until ICU discharge. Risk factors for IP were identified in the entire cohort. A matched nested case–control study was used to evaluate the excess risk of IP in decedents.Of the 3,499 patients, 69 with pneumothorax before ICU admission were excluded. Of the remaining 3,430 patients, 94 experienced IP within 30 days (42 due to barotrauma and 52 due to invasive procedures). The cumulative incidence of IP was 1.4% (95% confidence interval [CI], 1.0–1.8) on day 5 and 3.0% (95% CI, 2.4–3.6) on day 30. Risk factors for IP (hazard ratio [95% CI]) were body weight less than 80 kg (2.4 [1.3–4.2]), history of adult immunodeficiency syndrome (2.8 [1.2–6.4]), diagnosis of acute respiratory distress syndrome (5.3 [2.6–11]) or cardiogenic pulmonary edema at admission (2.0 [1.1–3.6]), central vein or pulmonary artery catheter insertion (1.7 [1.0–2.7]), and use of inotropic agents during the first 24 h (2.1 [1.3–3.4]). Excess risk of IP in decedents was 2.6 (95% CI, 1.3–4.9; P = 0.004).Iatrogenic pneumothorax is a life-threatening complication seen in 3% of ICU patients. Incorporating risk factors for IP into preventive strategies should reduce the occurrence of IP.