Objectives: The importance of health-related quality of life (HRQoL) in multiple sclerosis (MS) is widely acknowledged. In 2015, a multicenter study was launched to assess the HRQoL and coping styles of chronically ill persons in Germany. Aims of this paper are (i) to describe how persons affected by MS assess their HRQoL and (ii) find out sociodemographic and disease-specific determinants of HRQoL. Materials and methods: A quantitative survey (optionally per paper-pencil or online) was conducted between March and October 2015 in Germany. Recruitment ways were: the Federal and Regional Associations of the German Multiple Sclerosis Society (DMSG), medical practices specialized in neurology/MS, hospitals, public events, social networks, and self-help clearinghouses. To measure HRQoL the Multiple Sclerosis International Quality of Life (MusiQoL) Questionnaire and the short-form of the Fear of Progression Questionnaire (FoP-Q) were used. Results: 1,220 individuals with MS participated in the study. Frequent problems reported were related to activities of daily living as well as sentimental and sexual life. Multiple regression analyses identified disease severity and comorbidity – in different directions (positive and negative) – as the strongest factors in predicting activities of daily living, symptoms, sentimental and sexual life, and reject. The demographic variables sex, age, education and employment status also have different impact on the HRQoL. Conclusions: Using HRQoL measures can be feasible outcomes in addtion to clinical assessments of MS and other chronic diseases, and can help better managing the care. Some challenges have to be taken into account involving patients and the limitations of our empirical study.