Postoperative hypoxemia (POH) is common and primarily treated with temporary oxygen supplementation. Because the clinical impact of POH is sometimes presumed as minor, efforts to better understand and minimize it have been limited. Here, we hypothesized that, after adjusting for opioids received perioperatively and other confounders, the frequency of POH events (POH%) reported within the first 3 postoperative days (PODs) is associated with increased postoperative 1-year mortality. With prior institutional review board (IRB) approval, the Epic Clarity database was queried for all adult inpatient anesthesia encounters performed at our health system (1 academic and 2 community hospitals) from January 1, 2012 to March 31, 2016. Patients with multiple hospitalizations or subsequent surgeries within the same hospitalization were excluded. We classified patients based on the presence (POH) or not (No-POH) of ≥1 documented peripheral saturation of oxyhemoglobin (SpO2) ≤85% event of any duration occurring between the discharge from the postanesthesia care unit (PACU) until POD 3. Demographics, comorbidities, surgery duration, morphine milligram equivalents (OMME) administered perioperatively, respiratory therapies, intensive care unit (ICU) admission, and hospital length of stay (LOS) were also collected. Logistic regression was used to characterize the association between POH and 1-year postoperative mortality after adjusting for perioperatively administered opioids and other confounding factors. A total of 43,011 patients met study criteria. At least 1 POH event was reported in 10,727 (24.9%) patients. Of these, 7179 (66.9%) had ≥1 hypoxemic event on POD 1, 5340 (49.8%) on POD 2, and 3455 (32.3%) on POD 3. Patients with ≥1 POH event, compared to No-POH patients, were older, had more respiratory and other comorbidities, underwent longer surgeries, received greater opioid doses on the day of surgery and POD 1, and received more continuous pulse oximetry monitoring. POH patients required more frequent postoperative oxygen therapy, noninvasive ventilation (NIV), intubation, and ICU admission. One-year postoperative mortality occurred in 4.4% of patients with ≥1 POH and 3.0% of No-POH patients (P < .001). After adjusting for confounding factors, for every 10% increase in the frequency of SpO2 ≤85% readings, the odds of postoperative 1-year mortality were 1.20 (95% confidence interval [CI], 1.11-1.29; P < .001). Perioperative opioids were not independently associated with increased 1-year mortality. After adjusting for perioperative opioids and other confounders, moderate/severe POH within the first 3 PODs was independently associated with increased 1-year postoperative mortality. Increased efforts should be directed to understand if efforts to detect and reduce POH lead to improved patient outcomes.