Background Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system (CNS). It is immunologically induced in genetically susceptible individuals. Proinflammatory cytokines play an important role as genetic polymorphisms in their genes might be involved in the susceptibility and pathogenesis of MS. Objective In this study, our goal was to analyze the association between the gene polymorphisms in interleukin-16 (IL-16) (rs4072111 C/T), tumor necrosis factor-α (TNF-α) -308 G/A (rs1800629 G/A) and IL-18 -607 C/A (rs1946518 C/A) and the susceptibility and clinical features of MS in an Egyptian cohort. Methods We genotyped these genetic polymorphisms in 150 subjects including 93 patients with MS and 57 unrelated healthy subjects. We employed polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) method for determining the IL-16 (rs4072111 C/T) and TNF-α -308 G/A (rs1800629 G/A) polymorphisms, and the allele- specific polymerase chain reaction (AS-PCR) method for IL-18-607 C/A (rs1946518 C/A) polymorphism. Results The IL-16 (rs4072111 C/T) polymorphism was not polymorphic in both MS patients and the healthy volunteers. For the TNF-α-308 G/A (rs1800629 G/A) polymorphism, the mutant AA genotype and A allele are not associated with the susceptibility of MS, however, associated with the severity and disability progression of the disease. We observed a statistically significant increase in the mean values of Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) in patients with AA genotype and A allele compared with those of genotypes GG and GA, and the G allele, and regression analysis confirmed that this polymorphism is a predictor of disease disability using EDSS. For the IL-18 -607 C/A (rs1946518 C/A) polymorphism, the frequency of mutant AA genotype and A allele showed significant differences between the MS patients and healthy controls. Conclusion The TNF-α-308 AA genotype and A allele could be related to disability progression and severity of MS and the IL-18-607 AA genotype A allele could be related to susceptibility of the disease in the Egyptian cohort.