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This study determined the measurement properties of the HIV Disability Questionnaire (HDQ) on a sample of people living with HIV (PLWHIV) to validate this assessment in a resource-limited environment. A quantitative, descriptive, cross-sectional research design was used with PLWHIV on antiretroviral therapy (ART) for six months or more. Participants completed the HDQ, World Health Organisation Disability Assessment Scale (WHODAS 2.0) and the Medical Outcomes Study – Social Support Survey (MOS-SSS). Disability presence, severity and episodic scores on the HDQ were tested against the WHODAS 2.0 and MOS-SSS to determine convergent and divergent construct validity and internal consistency. Results for the HDQ were compared to four other populations from high-income countries. Of the sample of 498 participants, 68% were female, the median age was 41 years and 19% had a median of one concurrent health condition. Median HDQ scores were 24.63 for disability presence, 10.14 for disability severity and 15.94 for the episodic scale. Moderate correlations confirmed 92.8% of convergent a priori hypotheses, while 85.7% of divergent a priori hypotheses were accepted. Cronbach’s alpha for the HDQ scales ranged from 0.89 to 0.84. Results from the HDQ differed from those determined in Canada, Ireland, the United States and the United Kingdom, with presence and severity scores for the South African sample being lower. Episodic scores were higher, which may be related to the socio-economic context. The HDQ is reliable and valid for disability determination and may be used as a rehabilitation outcome measure for PLWHIV in South Africa.