Guidelines for the prescription of long-term oxygen therapy (LTOT) in hypoxemic COPD patients are based on two landmark studies in which survival was the primary outcome. Such patients are importantly symptomatic with poor health-related quality of life (HRQL) but the effect of LTOT on HRQL remains uncertain. We undertook a prospective longitudinal interventional study of consecutive COPD patients referred to our regional oxygen service; n = 43 fulfilling criteria and commenced on LTOT, n = 25 not fulfilling criteria and continued on standard care. HRQL was measured at baseline, 2 and 6 months. Both patient groups had severe COPD as defined by mean FEV1 < 35% predicted. At baseline the LTOT group demonstrated significantly worse HRQL as defined by the Chronic Respiratory Questionnaire (CRQ) (fatigue, emotional function, mastery and total scores), total generic Dartmouth COOP Charts and anxiety domain of the Hospital Anxiety and Depression scale. Significant improvements in HRQL were noted at 2 and 6 months in the LTOT group. Conversely the non-LTOT group demonstrated a progressive decline in HRQL. Using validated criteria for a minimal clinically significant improvement in CRQ, there were 28 (67%) and 26 (68%) 'responders' at 2 and 6 months respectively in the LTOT group. The introduction of LTOT to patients with severe COPD fulfilling standard criteria was associated with early significant improvements in HRQL with sustained or further response at 6 months.