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Introduction: Depression and the presence of a disability emerge as noteworthy predictors of the quality of life (QoL) in patients with multiple sclerosis (MS). In this article, we explore the relationship between disability status, depression, and quality of life in individuals with multiple sclerosis., Methods: A total of 150 patients participated in this cross-sectional study. A Persian translation of the Multiple Sclerosis Quality of Life-54 questionnaire was utilized to assess their health-related quality of life (QoL), while the patients' disability levels were measured using the Expanded Disability Status Scale. Additionally, we assessed patients' depression levels using the 21-item BDI-II scale. The questionnaire data were analyzed using SPSS version 25., Results: A total of 150 MS patients participated in the study, with a mean age of 33.4 years (SD = 3.1). The majority were female (n = 71.2 %). The mean EDSS score was 3.7 (SD = 1.8). In the correlation analysis, we found that EDSS scores were not significantly correlated with mental QoL (r = -0.180, p = 0.109), but were significantly correlated with lower physical QoL (r = -0.393, p 0.001). Depression scores were significantly correlated with mental QoL (r = -0.776, P 0.001) and physical QoL (r = -0. 726, P 0.001). The results reveal that both EDSS and Beck scores significantly affect mental and physical health, explaining 62 % and 60 % of their variances, respectively., Conclusion: Our findings indicate a significant relationship between physical quality of life and EDSS scores in MS patients. Higher EDSS scores consistently corresponded to more significant physical impact, as evidenced by higher impact ratings. Conversely, there was no clear association between EDSS scores and mental quality of life. Furthermore, increased depression levels were linked to reduced levels of both mental and physical well-being. These results emphasize the intricate interplay between the physical aspects of quality of life and their implications for the progression and severity of MS in patients., Competing Interests: Declaration of competing interest M.A.S and A.N.M: I have received educational, research grants, lecture honorarium, travel supports to attend scientific meetings from Biogen-Idec, Merck-Serono, Cinnagen, Zistdaru, Zahravi and Genzyme. The other authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)