BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease which impacts patients’ lives. Many studies in high-income countries have focused on their health-related quality of life (HRQoL). However, evidence of awareness of SLE and HRQoL in low- and middle-income countries is lacking. Therefore, this study aimed to identify the determinants of HRQoL of SLE patients in Vietnam, a lower-middle income country.MethodsThis cross-sectional study was conducted at the National Hospital of Dermatology and Venereology in 2019. A pre-tested structured questionnaire was used to collect data. It consisted of Short Form-36 to assess HRQoL which comprised physical and mental component summaries, Multidimensional Scale of Perceived Social Support, Satisfaction with Life Scale, and Mental Adjustment to SLE. Multiple linear regression was used to identify the determinants of HRQoL.ResultsOne hundred thirty four patients with SLE participated in this study. The majority of the patients were women (n = 126, 94.0%). The mean age of all participants was 37.9 years old (standard deviation [SD] 12.5). Of 134 participants, 104 (77.6%) were married. Older patients were more likely to have a lower score of mental component summary (B=-0.45, 95% CI -0.73, -0.17). Patients with more children were more likely to have a lower score of physical component summary (B=-5.14, 95% CI -9.27, -1.00). Patients who felt more helplessness or hopelessness were more likely to have lower scores of physical and mental component summaries (B=-1.85, 95% CI -2.80, -0.90; B=-1.69, 95% CI -2.57, -0.81). Also, patients who felt more anxious were more likely to have a lower score of mental component summary (B=-1.04, 95% CI -1.77, -0.32). Patients who were more satisfied with their lives were more likely to have higher scores of physical and mental component summaries (B = 1.07, 95% CI 0.50, 1.64; B = 1.08, 95% CI 0.55, 1.61).ConclusionFactors associated with lower HRQoL in Vietnam were feelings of helplessness or hopelessness, and burdens of parenting roles. However, social support can contribute to a higher HRQoL, such as information support, self-support groups, and daycare services provided at the community level.Supplementary InformationThe online version contains supplementary material available at 10.1186/s41927-023-00339-6.