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Background & aim: Loneliness is a common experience in people with MS that is associated with significant psychological consequences. Therefore, it is important to check the psychosocial status of people with MS patients. Accordingly, the aim of the present study was to investigate the mediating role of social loneliness in the relationship between self-compassion and psychological well-being. Methods: For this descriptive-correlational study, 220 patients with MS were selected by a convenience sampling method. Data were collected by using Psychological Well-Being Scales of Ryff's (PWB), Self-compassion Scale (SCS), and social loneliness (SLS). Finally, Data were analyzed by Pearson correlation and Structural Equation Model using SPSS software version 23 and AMOS version 24. Results: The results showed that the self-Compassion had a significant positive correlation with psychological well-being (r=0.66, p<0.01) and a significant negative correlation with social loneliness (r=-0.63, p<0.01). Also, There was a significant negative correlation between feelings of social loneliness with well-being psychological (r=-0.69, p<0.01). The indirect effect and the effect of total self-Compassion on psychological well-being were 0.26 and 0.86, respectively, Conclusion: The results showed that the feeling of social loneliness plays a mediating role in the relationship between self-compassion and psychological well-being. Therefore, it is possible to improve the psychological well-being of people with multiple sclerosis by improving social relationships.