Abstract: Polymorphisms of TLR genes could regulate and contribute functionally to innate immunity and inflammation. TLR2, a promiscous receptor recognizes Pathogen Associated Molecular Patterns from several microbes, bacterial, viral, protozoan and helminths. We demonstrate that monocytes of humans with deletion polymorphism in TLR2 gene (a 23 bp deletion in 5’ UTR region) respond more vigorously in vitro to several TLR2 ligands in comparison to those with insertion allele. Lower primates such as Rhesus monkeys and Baboon display ‘deletion’ genotype while insertion is found in higher primates viz., Orangutan, Chimpanzees and Gorilla. Enhanced inflammation is a hallmark of pathogenesis in human severe malaria leading to adverse prognosis and odds ratio of patients prone to develop severe malaira such as multi organ failure with del/del genotype was found to be very high. Based on induction of inflammatory cytokines by normal human PBMCs in vitro and circulating cytokine levels in cohorts of patients with severe P. falciparum malaria we propose that ‘insertion’ of a 23bp sequence in 5’UTR region of TLR2 gene could have led to moderated TLR2 induced inflammation thus offering survival advantage to higher primates and rendering them relatively refractory to multi-organ dysfunction in severe malaria.