Few cross-cultural measures are available to assess quality of life (QoL) in HIV/AIDS. A short form of the WHOQOL-HIV—the WHOQOL-HIV BREF—was developed and tested. Survey data from 1,923 HIV-positive adults (selected for age, gender and disease stage) were collected in 8 culturally diverse centres. The ‘best’ HIV-specific item was extracted from five HIV facets of the WHOQOL-HIV long form using information about item correlations with QoL, health and domains, item discriminant validity and centre problems. The five identified items were then integrated with the WHOQOL-BREF to complete the 31 item WHOQOL-HIV BREF. This short form shows good internal consistency reliability and discriminant validity for ‘known’ disease stages. Confirmatory Factor Analysis showed an overall good fit for a six domains model (Comparative Fit Index = 0.97), supporting scoring. Quality of life in different cultures is reported. A value of the WHOQOL-HIV short form is in monitoring QoL in multi-national clinical trials, and in clinical practice.