IMPORTANCE Despite suggestions of potential harm from unnecessary oxygen therapy, critically ill patients spend substantial periods in a hyperoxemic state. A strategy of controlled arterial oxygenation is thus rational but has not been validated in clinical practice. OBJECTIVE To assess whether a conservative protocol for oxygen supplementation could improve outcomes in patients admitted to intensive care units (ICUs). DESIGN, SETTING, AND PATIENTS Oxygen-ICUwas a single-center, open-label, randomized clinical trial conducted from March 2010 to October 2012 that included all adults admitted with an expected length of stay of 72 hours or longer to the medical-surgical ICU of Modena University Hospital, Italy. The originally planned sample size was 660 patients, but the study was stopped early due to difficulties in enrollment after inclusion of 480 patients. INTERVENTIONS Patients were randomly assigned to receive oxygen therapy to maintain PaO2 between 70 and 100mmHg or arterial oxyhemoglobin saturation (SpO2) between 94% and 98%(conservative group) or, according to standard ICU practice, to allow PaO2 values up to 150mmHg or SpO2 values between 97%and 100% (conventional control group). MAIN OUTCOMES AND MEASURES The primary outcomewas ICU mortality. Secondary outcomes included occurrence of new organ failure and infection 48 hours or more after ICU admission. RESULTS A total of 434 patients (median age, 64 years; 188 [43.3%] women) received conventional (n = 218) or conservative (n = 216) oxygen therapy and were included in the modified intent-to-treat analysis. Daily time-weighted PaO2 averages during the ICU stay were significantly higher (P