Abstract Background To enhance health care for chronically ill people, it is crucial to understand the impact of their disease on health-related quality of life (HRQoL). More than 240,000 people in Germany live with multiple sclerosis (PwMS), the most common immune-mediated neurodegenerative disease of the central nervous system. Little is known about HRQoL in PwMS in comparison to the general population and by subgroups. Methods In 2021, 6,928 statutorily-insured PwMS aged ≥18 years and living in the federal state of Lower Saxony, Germany, were invited to take part in an online survey. The German EQ-5D-5L value set was used to analyse HRQoL by index values. Descriptive subgroup analyses were conducted (age, sex) and compared to a general German reference population (Grochtdreis et al. 2019, DOI: 10.1007/s10198-019-01054-1). Mann-Whitney-U- or Kruskal-Wallis-tests were performed as appropriate. Results Of 1,935 respondents (response rate 27.9%), 1,916 PwMS were included in the current preliminary complete case analysis. HRQoL is reduced in PwMS compared to the general population: Mean (M) 0.67 vs. M 0.88, respectively. While no significant differences by sex were found in PwMS (male: M 0.66 vs. female: M 0.68, p = 0.1), HRQoL decreased with increasing age (p < 0.001). The reduction in HRQoL is more pronounced in PwMS than in the general population (difference between means 0.53 in 18-24 years old to ≥ 75 years old PwMS vs. 0.14 in the reference population, respectively). Conclusions PwMS report an overall lower level of HRQoL compared to the general population. Increasing age correlates with a substantial decrease of HRQoL in PwMS. Targeted research is needed to improve HRQoL of this vulnerable population. Key messages • The decline in HRQoL with increasing age is more pronounced in PwMS than in the general population in Germany. • Further research should focus particularly on the extent to which MS-related factors are solely attributable for the considerable decline of HRQoL in PwMS.