BACKGROUND: Main risk factor for the development of chronic obstructive pulmonary disease (COPD) is smoking, although only less than 1/3 of smokers develop clinically manifest COPD. COPD's progressive nature with high disability and mortality makes it plausible to detect it as early as possible thus allowing for an early intervention. The only tool for an early diagnosis that could be used on the global scale is spirometry, even though symptoms and deprivation of health related quality of life (HRQoL) precede relevant spirometric changes. Existing HRQoL questionnaires are too complicated or not developed for an early detection of COPD. The aim of our study was to develop a new simple HRQoL tool that will allow (alone or in combination with other markers) early detection of patients with COPD. METHODS: A multicenter prospective cohort study recruiting 500 subjects at risk for COPD (smokers/ex-smokers ≥20 pack-years, 40-65 years, both sexes, with no prior diagnosis of COPD) will be carried out in two phases: (1) cross-sectional - development and validation of a new questionnaire; and (2) prospective - follow-up of a cohort of patients at risk for COPD. Subjects were recruited by 25 GPs and assessed for COPD by dedicated pulmonologists in 7 hospital centers using a predefined protocol: HRQoL, history, physical, blood sampling, exhaled breath temperature (EBT), lung function, 6-min walk test (6MWT). Patients without COPD and those in GOLD stage 1 at initial assessment will be reassessed for disease progression by the same pulmonologist after 2 and 5 years. DISCUSSION: This is one of the first cohort studies attempting to establish the incidence of COPD in the pre-symptomatic stage before significant end organ damage. We intend to assess the validity, predictability and discriminative power ('healthy' smokers vs. pre-symptomatic phase in newly developed COPD) of newly developed HRQoL tool alone or in combination with other markers; EBT, lung function, 6MWT, genomics, transcriptomics, proteomics). We expect that the results of this study can improve our understanding of the development of COPD, identify some new underlying pathophysiological pathways, and offer to sensitive smokers/ex-smokers new preventive and early intervention measures thus improving the management of COPD.