Abstract Background The prevalence of multimorbidity is increasing worldwide, and older people with multimorbidity are frequent users of health care services. Since multimorbidity has a significant negative impact on Health-related Quality of Life (HrQoL) and is more common in older age it would be expected that factors related to HrQoL in this group might have been thoroughly researched, but this is not the case. Furthermore, it is important to look at old people living at home, considering the shift from residential to home-based care. Therefore, we aim to investigate factors that are related to HrQoL in older people with multimorbidity and high health care consumption, living at home. Methods This is a secondary analysis of a RCT study conducted in a municipality in south-eastern Sweden. The study had a longitudinal design with a two-year follow-up period assessing HrQoL, symptom burden, activities of daily living, physical activity and depression. Results In total, 238 older people with multimorbidity and high health care consumption, living at home were included (mean age 82, 52% female). A multiple linear regression model including symptom burden, activities of daily living and depression as independent variables explained 64% of the HrQoL. Higher symptom burden, lower ability in activities of daily living and a higher degree of depression were negatively related to HrQoL. Depression at baseline and a change in symptom burden over a two-year period explained 28% of the change in HrQoL over a two-year period variability. A higher degree of depression at baseline and negative change in higher symptom burden were related to a decrease in HrQoL over a two-year period. Conclusion In order to facilitate better delivery of appropriate health care to older people with high health care consumption living at home it is important to assess HrQoL, and HrQoL over time. Symptom burden, activities of daily living, depression and change in symptom burden over time are important indicators for HrQoL. Trial registration Clinicaltrials.gov identifier: NCT01446757, the trial was registered prospectively with the date of trial registration October 5th, 2011.