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Background: People with Multiple Sclerosis (PwMS) have reported a higher unemployment rate compared to the general population. The complexity of environmental-contextual factors, such as structural and functional social support, may influence employment status (ES). Objectives: to study the relationship between perceived social support and ES, assess the effects of potential mediators, and analyze how these predictors influence components of ES, including absenteeism, work harassment, negative work events, and the use of accommodations. Material and Method: 90 PwMS were recruited. A single-visit assessment included: the Medical Outcomes Study Social Support Survey (MOS-SSS), the Buffalo Vocational Monitoring Survey, the Symbol Digit Modalities Test (SDMT), patient-reported outcomes measuring depression (Beck Depression Inventory-II (BDI-II) and fatigue (Fatigue Severity Scale), and the EDSS. Results: Sixty-three (70%) of PwMS were employed. Mediation analysis revealed the involvement of BDI-II and SDMT in the relationship between social support and ES. The functional social support of friends had a significant effect on absenteeism and NWEs. Total functional support was related to harassment, while family support had a significant effect on accommodations. Conclusion: These results show that structural and functional social support, in relation to the clinical variables of the disease, increase the probability of employment and a better quality of work. Full article