The purpose was to compare and comment on use of the SF-36 and MOS-HIV instruments in studies of persons with HIV disease. Three medical information databases were searched to identify examples of HIV studies that included the MOS-HIV or SF-36. Thirty-nine and 14 published articles were identified for illustration in comparing the use of the MOS-HIV and SF-36 in HIV disease, respectively. Support for the reliability and construct validity of the MOS-HIV and SF-36 was found. Ceiling and floor effects were reported for both the MOS-HIV and SF-36; however, ceiling effects were more common for the MOS-HIV, in part due to fewer items in the physical, social, and role functioning domains. The MOS-HIV measures three domains hypothesized to be associated with the health deterioration of HIV disease not measured by the SF-36; however, these domains may not assess aspects of HIV disease that typify the majority of the persons with HIV disease today. National norms for the U.S. adult population (and other nations) are available for the SF-36. In addition, the SF-36 has been used in a wide variety of patient populations, enabling comparisons of HIV-infected persons with persons with other health conditions. No national norms for the MOS-HIV are available. We conclude that there is currently insufficient evidence in the literature to recommend the use of the MOS-HIV over the SF-36 in HIV-infected persons. Although the SF-36 is not targeted at HIV, it may be preferable to use the SF-36 over the MOSHIV due to fewer ceiling effects, availability of national norms, and the vast amount of data for other populations in the U.S. and around the world. Head-to-head comparisons demonstrating the unique value of the MOS-HIV over the SF-36 are clearly needed. More importantly, additional work needs to be directed at comparing the MOS-HIV and other putatively HIV-targeted instruments to one another to help demarcate aspects of HRQOL that are truly generic versus specific to HIV disease. Using both a generic and targeted HRQOL measure is a good general strategy, but this has not been a typical practice in studies of HIV because the MOS-HIV is so similar in content to the SF-36.