With the advent of highly active antiretroviral therapy (HAART), HIV-infected patients are living longer and are concerned not only with a treatment's ability to extend their life but also with the quality of the life they are able to lead. Regulatory authorities are also paying closer attention to the use of health-related quality-of-life (HR-QOL) measures in clinical trials and to the subsequent claims that are made based on the results. This paper reviews existing HR-QOL measures reported in the HIV/AIDS literature since 1990 and identifies those most worthy of consideration for use in future clinical trials.A comprehensive review following predefined selection criteria was conducted. Generic and HIV-targeted measures were assessed for content and practicality for the clinical trial setting. The generic measures were additionally reviewed for the ability to produce preference-based index scores and for the existence of normative general population data. Three generic and six HIV-targeted measures met these selection criteria and were then assessed more fully in terms of their development (HIV-targeted measures), psychometric properties and appropriateness for use in clinical trials.It was determined that each of the selected generic measures (i.e. Medical Outcomes Study [MOS] 36-Item Short Form Survey Instrument [SF-36], EQ-5D, Health Utilities Index [HUI]) could serve as a useful adjunct to an HIV-targeted measure in a trial. The Functional Assessment of HIV Infection (FAHI) and MOS-HIV health survey were deemed the two most appropriate HIV-targeted measures. Each of the measures can be self-administered in < or = 10 minutes and there was ample evidence of their excellent psychometric properties. However, they would not be optimal in all HIV-infected subgroups (e.g. treatment naive vs advanced; adolescents vs older adults) targeted for clinical trial interventions. Although there is no one best HR-QOL measure for use in HIV/AIDS clinical trials, based on our review criteria we identified three generic and two HIV-targeted candidate measures. However, these measures have their limitations and it is clear that greater consensus needs to develop regarding more effective and efficient approaches to HR-QOL measurement in HIV/AIDS clinical trials. Along with the increasingly complex HR-QOL measurement task resulting from changes in the HIV-infected population and shifts in the HR-QOL burden associated with HIV infection and its treatment over the past 25 years, it is increasingly important that HR-QOL outcomes become viable endpoints in HIV/AIDS clinical trials.