The extent to which a chronic obstructive pulmonary disease (COPD) patient is impaired in health-related quality of life (HRQoL) is only to a small extent reflected in clinical and demographical measures. As the influence of comorbidity on HRQoL is less clear, we investigated the added value of 23 common diseases in predicting HRQoL in COPD patients with mild to severe airways obstruction. COPD patients from general practice who appeared to have an forced expiratory volume in 1 sec/inspiratory vital capacity (FEV1/IVC) < predicted -1.64 SD, FEV1 <80% predicted, FEV1 reversibility < 12% and a smoking history, were included (n=163). HRQoL was assessed with the short-form-36 (SF-36) and the presence of comorbidity was determined by a questionnaire, which asked for 23 common diseases. All domains of the SF-36 were best predicted by the presence of three or more co-morbid diseases. FEV1 % predicted, dyspnoea and the presence of one or two diseases were second-best predictors. Co-morbidity explained an additional part of the variance in HRQoL, particularly for emotional functioning (delta R2=0.11). When individual diseases were investigated, only insomnia appeared to be related to HRQoL. As HRQoL is still only partly explained, co-morbidity and other patient characteristics do not clearly distinguish between COPD patients with severe impairments in HRQoL and COPD patients with minor or no impairments in HRQoL. Therefore, it remains important to ask for problems in daily functioning and well-being, rather than to rely on patient characteristics alone.