Though life expectancy of people living with HIV (PLHIV) is now comparable to that of HIV-negative persons, their health-related quality of life (HRQoL) lags behind. Lower HRQoL among PLHIV may vary meaningfully, shaped in part by social factors, including stigma. Using data from Positive Voices, a national cross-sectional probability survey of adults ≥18 years living with HIV and accessing HIV care services in England and Wales (N = 4,422), we conducted latent class analysis on responses to a HRQoL measure (problems with mobility, usual activities, self-care, pain/discomfort, anxiety/depression) to identify HRQoL patterns, followed by multinomial logistic regression to examine relationships between HRQoL classes and a 4-item measure of HIV-related stigma and discrimination in health care. Four classes emerged: All Problems (18% prevalence); Pain and Distress (18%); Pain and Mobility (9%); No Problems (55%). Scale scores of HIV-related stigma and discrimination in health care were positively, significantly associated with membership in the All Problems (adjusted odds ratio [aOR] = 2.16; 95% confidence interval [CI] = 1.94, 2.41), Pain and Distress (aOR = 1.62; CI = 1.46, 1.81), and Pain and Mobility classes (aOR = 1.33; CI = 1.16, 1.52) compared to the No Problems class. A similar trend was observed for individual stigma and discrimination items. HRQoL among PLHIV in England and Wales varies and may be underpinned or exacerbated by HIV-related stigma and discrimination in health care. Ensuring stigma-mitigation interventions reach all health care systems/providers and emotional support services reach all PLHIV may improve HRQoL for PLHIV.