The aim of this study is to explore whether self-esteem and social participation are associated with the physical and mental quality of life (Physical Component Summary, Mental Component Summary) and whether self-esteem can mediate the association between these variables. We collected information from 118 consecutive multiple sclerosis patients. Age, gender, disease duration, disability status, and participation were significant predictors of Physical Component Summary, explaining 55.4 percent of the total variance. Self-esteem fully mediated the association between social participation and Mental Component Summary (estimate/standard error = –4.872; p < 0.001) and along with disability status explained 48.3 percent of the variance in Mental Component Summary. These results can be used in intervention and educational programs.