Purpose: Paying attention to the factors affecting the psychological well-being of people with multiple sclerosis (PwMS) is of particular importance, hence the present study investigated the relationship between self-compassion and psychological well-being with the mediating role of resilience. Methods: This cross-sectional study was performed using an online survey in a sample of 410 PwMS registered with the Guilan MS Society (GMSS) of Iran. The study was conducted in 2021. A demographic questionnaire, Ryff 's Psychological Well-Being Scales (PWB), the Connor-Davidson Resilience Scale (CD-RISC), and the Self Compassion Scale Short Form (SCS-SF) were used to collect data. Data analysis was performed using structural equation modeling. Results:The model and data were sensibly in agreement. Moreover, bootstrap results showed that all direct path coefficients were significant (t ≥ 1.96). The direct effects of self-compassion and resilience on psychological well-being were significant, with standardized coefficients of 0.69 and 0.21. In addition resilience, with a coefficient of 0.73, was associated with psychological well-being. Furthermore, the indirect effect of self-compassion on psychological well-being with the mediating role of resilience was also confirmed (p ≤ 0.05). Conclusions:The administration of GCs may lead to changes in dopaminergic system activity (e.g. D 2 receptors activity), which significantly contribute to the predisposition to depression. Additionally, GCs therapy may cause changes in the activity of microRNAs (e.g. miR-124), which exacerbates symptoms of depression. Searching for specific changes in microRNA expression will provide clinically practical and easily applicable biomarkers of depression risk and new forms of pharmacotherapy in GC-induced depression.