BackgroundOne of the major challenges faced by people living with HIV (PLH) is the compromised quality of life due to the negative impact of HIV on their health. HIV/AIDS control effort should go beyond laboratory and lay more emphasis on improving the health-related quality of life (HRQoL) for PLH. The objective of this study is to evaluate the physical and mental HRQoL of PLH in rural China, and explore the relationship between HRQoL and individual- and family-level factors.MethodsA cross-sectional study was conducted among 522 PLH in Anhui, China. Participant’s sociodemographic characteristics, family status, and HIV-related factors were collected. Physical health summary score (PHS) and mental health summary score (MHS) of quality of life were measured. Multiple linear regressions were conducted to estimate the association of the individual- and family-level factors with MHS and PHS.ResultsMale were more likely to report a higher level of PHS and MHS than female (β = 0.123, P = 0.009; β = 0.150, P = 0.002). Age was significantly negatively associated with the PHS (β = − 0.232, P<0.001) when other variables were controlled. Family size remained negatively correlated with PHS (β = − 0.105, P = 0.021). Family annual income was significantly positively associated with PHS and MHS (β = 0.126, P = 0.003; β = 0.135, P = 0.002).ConclusionsFuture intervention should be carefully tailored to the specific needs of sub-populations (such as female and older PLH) considering their physical and mental HRQoL conditions. More attention and care should be provided to PLH with left-behind children in the family.