BACKGROUND Oxygen therapy is routinely administered to mechanically ventilated patients. However, there remains uncertainty about the optimal oxygen titration target in patients with the acute respiratory distress syndrome (ARDS). METHODS Prospectively identified adult patients meeting the Berlin definition of ARDS between 1st January 2014 and 13th December 2016 were analyzed. Oxygen exposure variables were collected at 6-hourly intervals. The primary exposure was the average time-weighted partial pressure of arterial oxygen (PaO2) calculated over a maximum of 7 days from meeting ARDS criteria. The primary outcome was ICU mortality. Univariable and multivariable logistic regression analyses were performed to assess the impact of exposure variables on clinical outcomes. Results are presented as odds ratio [95% confidence interval]. RESULTS 202 patients were included in the final analysis. Overall ICU mortality was 31%. The average time-weighted PaO2 during the first 7 days of ARDS was similar between non-survivors and survivors (11.3 kPa [10.2, 12.5] (84.8 mmHg [76.5, 93.8]) vs. 11.9 kPa [10.9, 12.6] (89.3 mmHg [81.8, 94.5]); p = 0.08). In univariable and multivariable analysis, average time-weighted PaO2 demonstrated a U-shaped relationship with ICU mortality. There was a similar relationship identified with hospital mortality. CONCLUSIONS In patients with ARDS, the predicted probability of both ICU and hospital mortality was lowest when the average time-weighted PaO2 was between 12.5 and 14 kPa (93.8-105.0 mmHg), suggesting this is a reasonable oxygenation target for clinicians to aim for.