- Severe malarial anemia (SMA) is a leading cause of pediatric morbidity and mortality in holoendemic Plasmodium falciparum transmission areas. Although dysregulation in cytokine production is an important etiology of SMA, the role of IFN-? in SMA has not been reported. As such, we investigated the relationship between IFN-? promoter polymorphisms [i.e., IFNA2 (A-173T) and IFNA8 (T-884A)], SMA, and functional changes in IFN-? production in children (n = 663; <36 months) residing in a holoendemic P. falciparum transmission region of Kenya. Children with SMA had lower circulating IFN-? than malaria-infected children without severe anemia (P = 0.025). Multivariate logistic regression analyses revealed that heterozygosity at -884 (TA) was associated with an increased risk of SMA [OR 2.80 (95 % CI 1.22-6.43); P = 0.015] and reduced IFN-? relative to wild type (TT; P = 0.038). Additional analyses demonstrated that carriage of the -173T/-884A (TA) haplotype was associated with increased susceptibility to SMA [OR 3.98 (95 % CI 1.17-13.52); P = 0.026] and lower IFN-? (P = 0.031). Follow-up of these children for 36 months revealed that carriers of TA haplotype had greater all-cause mortality than non-carriers (P < 0.001). Generation of reporter constructs showed that the IFNA8 wild-type -884TT exhibited higher levels of luciferase expression than the variant alleles (P < 0.001). Analyses of malaria-associated inflammatory mediators demonstrated that carriers of TA haplotype had altered production of IL-1?, MIG, and IL-13 compared to non-carriers (P < 0.050). Thus, variation at IFNA2 -173 and IFNA8 -884 conditions reduced IFN-? production, and increased susceptibility to SMA and mortality.