The assessment of quality of life (QOL) in HIV infection has emerged as being vital to research and clinical practice. This assessment is also a challenge due to the specific characteristics of the infection, the increased availability of therapeutics, as well as the epidemiological variability inherent to HIV infection. The purpose of this study was to investigate the psychometric properties of the European Portuguese version of the World Health Organization's QOL Instrument in HIV Infection (WHOQOL-HIV) and to test its performance in a sample of HIV-infected patients. The European Portuguese version of WHOQOL-HIV was administered in a sample of 200 HIV-positive patients. The patients also completed the Portuguese versions of Beck Depression Inventory (BDI) and Brief Symptom Inventory (BSI). The WHOQOL-HIV showed quite an acceptable internal consistency (Cronbach's α ranged from 0.86 to 0.95 across domains). Convergent validity with BDI and BSI was satisfactory for all domains (all r>0.50; p<0.001). Moreover, correlations between domains and between domains and overall QOL were all statistically significant (p<0.001). The reliability and validity studies of the European Portuguese version of the WHOQOL-HIV revealed good psychometric characteristics, which allows for the use of this version of WHOQOL in our country, and cross-cultural comparability.