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To compare the sensitivity to change of two HIV-health-related quality of life (HRQoL) questionnaires – the Medical Outcomes Study (MOS-HIV) and Multidimensional Quality of Life (MQOL-HIV) for use in clinical research.A sample of 296 HIV-infected patients starting or switching antiretroviral treatment were randomly assigned either the MOS-HIV or MQOL-HIV questionnaires at baseline and after 3 months of treatment. Ceiling and floor effects were evaluated. Sensitivity to change was assessed by comparing the percentage of dimensions with statistically significant pre–post-treatment changes and the effect sizes in those groups of patients who reported improvement and no change in self-report questions (overall, physical, mental and social health status) and clinical characteristics (number of opportunistic infections, number of symptoms, viral load level and CD4+ count).Ceiling effects were found in HRQoL scores at baseline and after 3 months of treatment in Pain (42.3-41.6%), Role Function (73.1–77.6%) and Social Function (60.9–63%) on MOS-HIV subscales, and in Social Support (38.2–37.6%) and Partner Intimacy (38.2–33.7%) on MQOL-HIV. For patients who improved in self-reported and objective clinical indicators of health status, mean percentage of dimensions with statistically significant pre–post-treatment changes was 86.4% on MOS-HIV and 50% on MQOL-HIV, where mean standardized effect size was 0.45 on MOS-HIV and 0.33 on MQOL-HIV for the total of dimensions.Based on sensitivity to change the results suggest that for 3 months both questionnaires can be used, but the MOS-HIV is more sensitive than the MQOL-HIV for use in clinical research.