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Abstract: The role of nitric oxide (NO) in the pathogenesis of cerebral malaria is controversial. Of the three isoforms of nitric oxide synthases (NOS), though iNOS expression is the major source of NO level in vivo, nNOS is the main isoform constitutively expressed in the neural tissues. However, there has been no investigation of the role of polymorphisms of the nNOS gene in the etiology of cerebral malaria. We have analyzed two single nucleotide polymorphisms (SNPs) of nNOS gene (−84G→A and 276C→T), responsible for decreased basal transcriptional activity, in 200 patients with mild Plasmodium falciparum malaria and 170 patients with cerebral malaria. Our results showed a significant association of AG genotype (OR=1.83, 95%CI=1.19–2.78, P =0.007) and AA genotype (OR=3.86, 95%CI=1.42–10.5, P =0.007) of nNOS −84G→A substitution with cerebral malaria. Interestingly, when the nNOS variant genotypes were combined together for analysis, a significantly increased risk of cerebral malaria was associated with −84(AG+AA)/276(CT+TT) genotype (OR=2.59, 95%CI=1.46–4.60, P =0.0016) and −84(AG+AA)/276(CC) genotype (OR=1.89, 95%CI=1.08–3.32, P =0.0334). The −84A seems to be a putative risk allele on the susceptibility to cerebral malaria and low nitric oxide production might have contributed to the development of cerebral malaria. [Copyright &y& Elsevier]