Background: Multiple Sclerosis is an inflammatory-demyelinating disease of the central nervous system that may produce severe levels of disability in the long term. This disease affecting more than 2 million people worldwide and it is the second leading cause of disability in young adults after trauma. Self-management is crucial to managing individuals with multiple sclerosis as advance their prognosis by learning about many aspects of the illness as well as closely monitoring their own health with their care providers. The study was aimed to evaluate the effect of self-management guidelines on knowledge, fatigue, self-efficacy, and medications adherence among patients with multiple sclerosis. Study design: A quasi-experimental design was applied in the current study. Setting: This study was conducted at multiple sclerosis outpatient clinic affiliated to Ain Shams University Hospital; Egypt. Sample: A Purposive sample of 75 adult patients from both sex with MS. Tools of data collection: data were collected using 7 tools as follow: 1-Patient interviewing questionnaire, 2- Multiple sclerosis knowledge questionnaire, 3-Fatiueg severity scale, 4-Self efficacy scale, 5-Morisky medication adherence scale, 6- Self-management scale-revised, and 7-Expanded disability status scale. Results:  The findings revealed statistically significant relation between self-management, Knowledge, Fatigue, Self-Efficacy and Medications Adherence among patients with multiple sclerosis pre and post implementation of self-management guidelines. While there was a positive statistically significant correlation regarding the measured variables of self-management guidelines. Conclusion: The significance of developing effective self-management strategies to reduce the disease consequences and improve therapeutic adherence despite the functional limitation imposed by the disease, greater attention to physiological and psychological aspects might be considerable in ensuring a greater state of well-being.  Recommendations: Accomplishing a periodic patient's self-management educational program to provide healthy lifestyle among patients with multiple sclerosis. Nurses can act as advocate through aiding patients to overwhelmed physical, cognitive and psychosocial obstacles to treatment.