Importance: Postoperative pulmonary complications (PPCs), a leading cause of poor surgical outcomes, are heterogeneous in their pathophysiology, severity, and reporting accuracy. Objective: To prospectively study clinical and radiological PPCs and respiratory insufficiency therapies in a high-risk surgical population. Design, Setting, and Participants: We performed a multicenter prospective observational study in 7 US academic institutions. American Society of Anesthesiologists physical status 3 patients who presented for noncardiothoracic surgery requiring 2 hours or more of general anesthesia with mechanical ventilation from May to November 2014 were included in the study. We hypothesized that PPCs, even mild, would be associated with early postoperative mortality and use of hospital resources. We analyzed their association with modifiable perioperative variables. Exposure: Noncardiothoracic surgery. Main Outcomes and Measures: Predefined PPCs occurring within the first 7 postoperative days were prospectively identified. We used bivariable and logistic regression analyses to study the association of PPCs with ventilatory and other perioperative variables. Results: This study included 1202 patients who underwent predominantly abdominal, orthopedic, and neurological procedures. The mean (SD) age of patients was 62.1 (13.8) years, and 636 (52.9%) were men. At least 1 PPC occurred in 401 patients (33.4%), mainly the need for prolonged oxygen therapy by nasal cannula (n = 235; 19.6%) and atelectasis (n = 206; 17.1%). Patients with 1 or more PPCs, even mild, had significantly increased early postoperative mortality, intensive care unit (ICU) admission, and ICU/hospital length of stay. Significant PPC risk factors included nonmodifiable (emergency [yes vs no]: odds ratio [OR], 4.47, 95% CI, 1.59-12.56; surgical site [abdominal/pelvic vs nonabdominal/pelvic]: OR, 2.54, 95% CI, 1.67-3.89; and age [in years]: OR, 1.03, 95% CI, 1.02-1.05) and potentially modifiable (colloid administration [yes vs no]: OR, 1.75, 95% CI, 1.03-2.97; preoperative oxygenation: OR, 0.86, 95% CI, 0.80-0.93; blood loss [in milliliters]: OR, 1.17, 95% CI, 1.05-1.30; anesthesia duration [in minutes]: OR, 1.14, 95% CI, 1.05-1.24; and tidal volume [in milliliters per kilogram of predicted body weight]: OR, 1.12, 95% CI, 1.01-1.24) factors. Conclusions and Relevance: Postoperative pulmonary complications are common in patients with American Society of Anesthesiologists physical status 3, despite current protective ventilation practices. Even mild PPCs are associated with increased early postoperative mortality, ICU admission, and length of stay (ICU and hospital). Mild frequent PPCs (eg, atelectasis and prolonged oxygen therapy need) deserve increased attention and intervention for improving perioperative outcomes.