Background: Patients with multiple sclerosis (MS) have symptoms that affect all facets of their lives; the most prevalent of these symptoms are pain and fatigue, which significantly lower their quality of life. The disease's complexity, the challenge of determining appropriate treatment, and the variety of symptoms underscore the gravity of the situation and the importance of including complementary interventions along with pharmacological therapy. The Zone foot reflexology massage (ZFRM) is one of the most popular complementary interventions that seem to be low-risk, adaptable, inexpensive, easy to use, and quite effective at decreasing pain and fatigue in several trials. Study aim: Evaluate the responsiveness of pain and fatigue of patients with MS to the Zone foot reflexology massage. Design: A quasi-experimental design. Setting: Multiple Sclerosis clinic belonging to the Neurological Diseases Outpatient Clinic, Zagazig University Hospitals, Al Sharqia Governorate, Egypt. Subject: A purposive sample of 60 adult patients with MS randomly assigned into two equal groups. Tools: A structured interview questionnaire, a visual analog scale, and a fatigue severity scale. Results: A statistically significant difference and decrease were observed in pain mean scores (p = 0.005 & 0.001) and fatigue mean scores (p = 0.004 & 0.001) of study group patients compared to the control group post-8 th and 12 th week, respectively, of Zone foot reflexology massage intervention. Conclusions: The pain and fatigue of patients with MS respond positively to Zone foot reflexology massage sessions, which reflect the significant effect of Zone foot reflexology massage in decreasing and improving the pain and fatigue of those patients. Recommendations: Zone foot reflexology massage should be a key component of provided care for patients with MS in addition to pharmacological treatments. Keywords: Multiple sclerosis, Pain, Fatigue, Zone foot reflexology massage.