OBJECTIVES: There are a number of instruments to describe severity and progression of multiple sclerosis, which are increasingly used as endpoints to assess the effectiveness of therapeutic interventions. We examined to what extent the psychometric properties of the two accepted instruments - EDSS and MSFC – meet the methodological standards and what value they  have in clinical trials. METHODS: We conducted a systematic literature search in relevant databases [MEDLINE (PubMed), ISI Web of Science, EMBASE, PsycINFO & PSYNDEX, CINAHL] yielding 3,860 results. The identification of relevant full-text publications was conducted using abstract and then full-text reviews. RESULTS: For evaluation of psychometric properties (validity, reliability, sensitivity of change) of EDSS and MSFC, 120 relevant full-text publications were identified, 54 of them assessed the EDSS, 26 the MSFC and 40 included both instruments. The EDSS has some documented weaknesses in reliability and sensitivity to change. For the MSFC, the main limitations are the learning effects and the z-scores method used to calculate the total score. However, the methodological criterion of validity applies sufficiently for both instruments. For use in clinical studies, we found that the EDSS has been preferred as a primary and secondary outcome measure in recent studies (50 EDSS, 9 MSFC). CONCLUSIONS: Recognizing their strengths and weaknesses, both EDSS and MSFC are suitable to detect the effectiveness of clinical interventions and to monitor the disease progress. Almost all publications identify the EDSS as the most widely used tool to measure disease outcomes in clinical trials. Despite some limitations, both instruments are accepted to generate "hard endpoints". In no publication, EDSS or MSFC are discussed as surrogate parameters. A great advantage of the EDSS is the international acceptance (e.g. by EMA) as a primary endpoint in clinical trials and its broad use in trials, enabling cross-study comparisons.