Abstract Background The assessment of functioning and disability is an important part of the clinical evaluation, since it measures disease burden and reflects the effectiveness of therapeutic planning and interventions. The aim of the current study was to develop such a self-report instrument on the basis of a review of the literature, and compatible with the WHO approach. Material and methods The review of the literature led to the development of the Global Disability Scale (Glo.Di.S) with 25 items assessing different aspects of disability. The study sample included 728 persons from vulnerable populations (homeless, jobless, very low income, single parent families etc.; (29.12% males and 70.88% females; aged 55.96 ± 15.22 years). The protocol included also the STAI and the CES-D. The statistical analysis included factor analysis item analysis and ANCOVA. Results The factor analysis revealed the presence of 4 factors explaining 71% of total variance (Everyday functioning, Social and interpersonal functioning, Severity and Mental disability). Chronbach’s alpha for the whole scale was 0.95 and for subscales were 0.74–0.94. Discussion The results of the current study suggest that the Glo.Di.S. has the potential to serve as a reliable and valid tool for assessing functioning and disability. Further research is needed to prove that it could be useful across countries, populations and diseases, and whether it provides data that are culturally meaningful and comparable. It can be used in surveys and in clinical research settings and it can generate information of use in evaluating health needs and the effectiveness of interventions to reduce disability and improve health.