To explore the hypothesis that angiotensin II may play a role in the susceptibility to cerebral malaria (CM), we performed a genetic association study of malaria patients in Orissa, India analyzing three SNPs (ACE2 C→T, iNOS C→T, eNOS Glu→Asp) and two I/D polymorphisms (ACE I/D and IL-4 B1/B2). Our results showed that the ‘D’ allele of ACE I/D polymorphism, responsible for increased Ang II production had a significant association with mild malaria and the ACE2 C→T substitution had gender specific effect of possibly reduced expression of ACE2 in presence of ‘T’ allele in women leading to increased level of Ang II and hence protection against CM. Combined genotype analysis of eNOS Glu→Asp substitution responsible for increased NO production in Plasmodium falciparum infected individuals and ACE I/D polymorphism also showed stronger association of (Glu-Asp+Asp-Asp/ID+DD) genotypes with mild malaria (P<0.0001). Whether by its antiplasmodial activity and/or by some unknown mechanisms, Ang II protects from susceptibility to cerebral malaria remains to be investigated. These genetic findings may contribute to the understanding of malaria pathogenesis.