To design a Health-related Quality of Life (HRQoL) instrument for HIV-infected people in the era of highly active antiretroviral therapy (HAART). The self-administered questionnaire was developed by an Italian network including researchers, physicians, people living with HIV, national institutions and community-based organizations (CBO) through several steps: (1) review of existing HRQoL literature and questionnaires for HIV-infected people; (2) selection of relevant domains measuring HRQoL in HIV-infected people, and identification of new domains related to new aspects of HRQoL concerning HAART-treated individuals; (3) conduction of two pre-test analyses in independent groups of Italian HIV-positive people (n approximately =100) distributed throughout the country. The objectives of the first pre-test were to verify the usefulness of the questionnaire, to construct a form easily understandable by everyone, to define the domains and their significance; the second pre-test aimed at evaluating and reshaping the questionnaire based on a statistical analysis of the outcomes of first pre-test; (4) validation analysis. A large cohort of people with HIV infection was recruited for the last step. The internal consistence reliability (Cronbach's alpha) was >or=0.70 for all domains. Most domains had Cronbach's coefficient >0.80. All domains demonstrated convergent and discriminant validity. The final version of ISSQoL includes two sections: HRQoL Core Evaluation Form (9 domains) and Additional Important Areas for HRQoL (6 domains). The ISSQoL was administered together with two additional forms: a Daily Impact of Symptoms Form and a Demographic Information Form. The Additional Important Areas for HRQoL include social support, interaction with medical staff, treatment impact, body changes, life planning, and motherhood/fatherhood. The data reported in the present paper provide preliminary evidence of the reliability and validity of the ISSQoL questionnaire for the measurement of HRQoL in HIV-infected people. The direct involvement of HIV-positive people in all the phases of the project was a key aspect of our work.