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Adipocytokines such as leptin (LEP) and adiponectin (ADIPOQ) represent a link between metabolism, nutritional status and immune responses. The present study aimed to determine the possible association between single nucleotide polymorphisms of LEP and ADIPOQ genes with multiple sclerosis (MS).Single nucleotide polymorphisms in LEP (rs2167270 or 19G > A and rs7799039 or −2,548G > A) and ADIPOQ (rs1501299 or +276G > T and rs266729 or −11,377C > G) were genotyped in 305 patients and 255 healthy individuals using polymerase chain reaction-restriction fragment length polymorphism. Sera levels of leptin and adiponectin were measured using enzyme-linked immunosorbent assay.The frequencies of low leptin producer rs2167270GG genotype and rs2167270G allele were significantly lower in patients with MS compared to those of controls (for GG genotype: 39.7% and 49.8%, respectively; P = 0.01; for G allele: 63.3% and 68.8%, respectively; P = 0.05). Both polymorphisms in ADIPOQ did not show any significant association with disease susceptibility, though after gender categorization the frequency of high adiponectin producer rs1501299TT genotype and rs1501299T allele were significantly higher in male controls compared to male patients (TT genotype: P = 0.006; T allele: P = 0.006). Additionally, rs1501299TT genotype in ADIPOQ was associated with susceptibility to primary progressive multiple sclerosis (PP-MS) (P = 0.02). Moreover, while the sera levels of leptin were only different between male patients and controls (P = 0.05), adiponectin levels were significantly higher in total and female healthy controls (P < 0.001, P = 0.002, respectively).Our findings provide evidence to support the hypothesis that functional ADIPOQ and LEP gene polymorphisms are associated with susceptibility to MS and its clinical forms.