Background: The role of adipokines such as leptin and adiponectin in regulating the immunity has been documented, however data concerning their consequence on multiple sclerosis (MS) Egyptian patients are deficient. The aim of this study is to demonstrate the serum levels of leptin and adiponectin in MS patients and to assess their association with disease disability and severity. A case–control study including 60 subjects (30 MS patients and 30 age, sex and body mass index-matched healthy controls) was performed. Results: Serum leptin level was significantly higher among MS patients than controls (P < 0.001) while adiponectin was not significantly elevated in MS patients (P = 0.24). There was a significant positive correlation between leptin levels with MS disability (Expanded Disability Status Scale) (r = 0.678; P < 0.001), severity (Multiple Sclerosis Severity Score) (r = 0.631; P < 0.001) and progression (progression index) (r = 0.461; P = 0.01). There was no statistically significant correlation between adiponectin with disease disability, severity or progression. Conclusions: MS patients had significantly higher serum leptin levels and insignificant adiponectin levels compared to controls. Leptin has a potential role in multiple sclerosis disability and severity. However, adiponectin is not useful as a biomarker of MS disease, disability and severity. Keywords: Multiple Sclerosis, Leptin, Adiponectin, Disability, EDSS, MSSS