This study investigated how HIV-related shame is associated with health-related quality of life (HRQoL) in older people living with HIV (PLHIV). Structural equation modeling tested whether HIV-related shame was associated with three dimensions of HRQoL (physical, emotional, and social well-being) and whether there were significant indirect associations of HIV-related shame with the three HRQoL dimensions via depression and loneliness in a sample of 299 PLHIV >= 50 years old. Results showed that depression and loneliness were key mechanisms, with depression at least partially accounting for the association between HIV-related shame and both emotional and physical well-being, respectively, and loneliness accounting for the association between HIV-related shame and social well-being. HIV-related shame appears to be an important correlate of HRQoL in older PLHIV and may provide a promising leveraging point by which to improve HRQoL in older PLHIV.