Background: Self-management is the cornerstone for controlling multiple sclerosis. As one's sense of meaning in life and his/her relationship with a higher power, spiritual well-being is an important coping resource in some chronic diseases. However, little is known about the role of spiritual well-being in self-management of people diagnosed with multiple sclerosis. Objectives: This study was aimed to assess the relationship between spiritual well-being and self-management among Iranian people with multiple sclerosis. Patients and Methods: Two hundred ninety-one people diagnosed with multiple sclerosis belonging to the Multiple Sclerosis Society of Mashhad, Iran, participated in this cross-sectional analytical study conducted in 2014. Demographic information was collected by using a demographic form. The multiple sclerosis self-management scale-revised (2011), developed by Bishop and Frain, was used to evaluate self-management of multiple sclerosis symptoms. Spiritual well-being of participants was assessed by using the spiritual well-being questionnaire developed by Paloutzian and Ellison in 1983. Descriptive statistic and inferential statistical methods including Pearson and Spearman's coefficient, stepwise multiple regression, independent t-test, Mann-Whitney U test, one-way ANOVA, and Kruskal-Wallis test were employed by using SPSS, version 16.0. The significance level was set at P ≤ 0.05. Results: Overall, the participants reported moderate levels of self-management and spiritual well-being as recorded on the multiple sclerosis self-management scale-revised and the spiritual well-being questionnaire. There was a significant correlation between the participants' spiritual well-being and self-management scores (r = 0.59, P < 0.001). Furthermore, participants' self-management was significantly correlated with existential health (r = 0.52, P < 0.001) and religious health (r = 0.57, P < 0.001). Finally, 40% of the variance of self-management was explained by three factors: spiritual well-being, marital status, and job type (R 2 = 0.4, F (3, 286) = 65.82, P < 0.001). Conclusions: Designing strategies to improve the spiritual well-being of people with multiple sclerosis can result in improved selfmanagement of the disease. In designing such programs, special attention should be paid to the patients' demographic characteristics such as employment type and marital status.