Cognitive and psycho-physiological condition in patients with long-term domiciliary oxygen therapy (DOT) remains uncertain. A cross sectional analysis was performed to investigate the age-related changes in cognitive and psycho-physiologic functions in patients with chronic respiratory failure receiving long-term DOT. Two expert practitioners visited the patient's home and examined them for analysis of cognitive function, emotional status, physical activity and degree of dyspneic sensation. One hundred and thirty-five patients completed the study. Control data from a cohort of 718 community dwellers were also included in this study. Male patients had significantly higher rates of chronic obstructive pulmonary disease (71% vs 47%, p = 0.001), lower values of forced expiratory volume in one second (FEV1.0) % (49.7 +/- 10.3 [standard deviation, S.D.] vs 66.0 +/- 7.5% predicted, p = 0.002) and higher Borg score, an indicator of dyspneic sensation, during daily exercise (3.2 +/- 0.8 [S.D.] vs 1.4 +/- 0.6, p = 0.01) compared with female patients. Linear regression analysis based on mean Mini-Mental State Examination scores, an indicator of cognitive function, showed that age-related cognitive decline was more pronounced in female patients than in female controls (-0.524/year, R2 = 0.426 vs -0.120/year, R2 = 0.027, p < 0.0001), while there was no significant difference between male patients and male controls (-0.156/year, R2 = 0.054, vs -0.077/year, R2 = 0.016, p = 0.231). These results demonstrate that age-related cognitive decline is more exaggerated in female patients receiving long-term DOT which should be taken into consideration in caring for patients with chronic respiratory failure.