The relationship between tissue depletion and decreased exercise performance has been well established in patients with COPD. In this study we investigated the influence of the pattern of tissue depletion on health related quality of life (HRQL) and their mutual relationship with exercise capacity and dyspnoea. Patients with low body weight and/or low fat-free mass (FFM; using bioelectrical impedance) were categorized in three groups according to type of tissue depletion: loss of both FFM and Eat mass (FM), and loss of FFM or FM only. Handgrip strength (HGS) was used as a functional outcome measure of tissue depletion. Exercise performance was assessed by 12 min walking distance (12MWD) and dyspnoea by visual analogue scale (VAS). HRQL was measured with the St George's Respiratory Questionnaire (SGRQ) and the Medical Psychological Questionnaire for Lung diseases (MPQL). Patients with depletion of FFM irrespective of body weight showed greater impairment in 12MWD, HGS, the 'activity' and impact' scores of the SGRQ and the domain 'invalidity' of the MPQL, in comparison with depleted patients with relative preservation of FFM. Exercise performance and dyspnoea were also significantly related to these subscores of HRQL. In addition, dyspnoea related significantly to the domain 'symptoms' of the SGRQ. Tissue depiction pattern remained significantly related to SGRQ-scores and the domain 'invalidity' of the MPQL when dyspnoea and walking distance were added to the model as a covariates. Tissue depletion is an important determinant of HRQL independent of exercise capacity and dyspnoea.