Summary Background Palliative oxygen therapy is widely used for treatment of dyspnoea in individuals with life-limiting illness who are ineligible for long-term oxygen therapy. We assessed the effectiveness of oxygen compared with room air delivered by nasal cannula for relief of breathlessness in this population of patients. Methods Adults from outpatient clinics at nine sites in Australia, the USA, and the UK were eligible for enrolment in this double-blind, randomised controlled trial if they had life-limiting illness, refractory dyspnoea, and partial pressure of oxygen in arterial blood (PaO2) more than 7·3 kPa. Participants were randomly assigned in a 1:1 ratio by a central computer-generated system to receive oxygen or room air via a concentrator through a nasal cannula at 2 L per min for 7 days. Participants were instructed to use the concentrator for at least 15 h per day. The randomisation sequence was stratified by baseline PaO2 with balanced blocks of four patients. The primary outcome measure was breathlessness (0-10 numerical rating scale [NRS]), measured twice a day (morning and evening). All randomised patients who completed an assessment were included in the primary analysis for that data point (no data were imputed). This study is registered, numbers NCT00327873 and ISRCTN67448752. Findings 239 participants were randomly assigned to treatment (oxygen, n=120; room air, n=119). 112 (93) patients assigned to receive oxygen and 99 (83) assigned to receive room air completed all 7 days of assessments. From baseline to day 6, mean morning breathlessness changed by -0·9 points (95 CI -1·3 to -0·5) in patients assigned to receive oxygen and by -0·7 points (-1·2 to -0·2) in patients assigned to receive room air (p=0·504). Mean evening breathlessness changed by -0·3 points (-0·7 to 0·1) in the oxygen group and by -0·5 (-0·9 to -0·1) in the room air group (p=0·554). The frequency of side-effects did not differ between groups. Extreme drowsiness was reported by 12 (10) of 116 patients assigned to receive oxygen compared with 14 (13) of 108 patients assigned to receive room air. Two (2) patients in the oxygen group reported extreme symptoms of nasal irritation compared with seven (6) in the room air group. One patient reported an extremely troublesome nose bleed (oxygen group). Interpretation Since oxygen delivered by a nasal cannula provides no additional symptomatic benefit for relief of refractory dyspnoea in patients with life-limiting illness compared with room air, less burdensome strategies should be considered after brief assessment of the effect of oxygen therapy on the individual patient. Funding US National Institutes of Health, Australian National Health and Medical Research Council, Duke Institute for Care at the End of Life, and Doris Duke Charitable Foundation.