Introduction Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Human Major Histocompatibility complex (HLA) class I and II genes are associated with MS pathogenesis. Natural killer cell receptors (KIRs) bind to different MHC class I molecules activating NK cells to produce immune-regulatory cytokines. Sphingosine 1-phosphate receptor 1 (S1PR1) polymorphism and increasing IL-17 levels in blood of MS patients associate with non­responding to fingolimod treatment. Aim: To investigate HLA class I and II alleles, MOG (V142L) variant, KIR receptor genes, S1PR1 gene polymorphisms and a possible biomarker, serum IL-17, association with MS in Iranian patients. Material and methods: 489 patients and 350 controls from Iran were recruited. PCR, Direct Sanger sequencing, ELISA, and PAGE, Real time PCR were applied for genotyping. Statistical analysis such as Chi squared test, independent sample t-test, Principal component analysis (PCA) and Logistic regression analysis, was performed to identify the associations of traits with MS. Bonferroni correction and Power calculation of study was calculated. Results Iranian Multiple Sclerosis (IRAMS) database containing 247 parameters of patients was generated. Association between HLA-DRBl*1501 (P=3.70xl0-5, OR=2.10 (95% CI: 1.50-3.00)) and HLA-A02 (P= 0.014, OR= 0.671 (95% CI: 0.489-0.922)) with MS was observed. Significant association (P<0.05) between HLA class I, II with motor symptoms, bladder dysfunction, optic symptoms, and neuropsychological signs was shown. There was significant association between HLA-C6 allele and MS (P= 0.027 and OR= 1.445 (1.040-2.007), but not between KIRs gene variants and MS. Respond to fingolimod was not associated with either S1PR1 polymorphism or IL-17 levels. Discussion This study has shown clear association between genetic variants and MS related traits. Novel variants in S1PR1 have been identified.