Morphological changes induced by HIV-related lipodystrophy profoundly affect body image and influence health-related quality of life. Measurements of health-related quality of life in patients with lipodystrophy are complex due to a lack of consensus on the definition of lipodystrophy, a lack of appropriate methods to capture the impact of body fat changes, and the subjective perception of those changes by patients. This review describes the different tools that have been used to assess quality of life in patients with lipodystrophy, and critically analyzes published papers on health-related quality of life. With regard to facial lipoatrophy, the most stigmatizing condition of lipodystrophy, we have analyzed the impact of reconstructive plastic surgery on patient-related outcomes and health-related quality of life. A better knowledge of the associations between lipodystrophy and health-related quality of life will allow us to understand the burden of long-term toxicities of antiretroviral therapies as well as to identify novel patient-related endpoints useful in assessing the efficacy of lipodystrophy treating programs.