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Alpha+-thalassaemia is well known for conferring partial protection to against severe malaria. On the other, Glutathione –S-transferase (GST) polymorphism has recently been associated to severe malaria in children. A retrospective cross sectional study was carried out to determine the relationship between genotypic polymorphisms of alpha+-thalassaemia and glutathione-S-transferase in children with severe malaria. A total of 148 DNA samples from children aged between 1 and 15 years with mild and severe malaria were retrieved and determined by polymerase chain reaction. Children with Glutathione-S-transferase-pi1 (GSTP1)-polymorphism were observed to have three fold risk (OR = 2.9; 95% CI =1.3- 6.1; P = 0.006) of developing severe malaria compared to mild malaria in Mnyuzi-Korogwe, north-eastern, Tanzania. In the presence of Glutathione- S-transferase-pi1 polymorphism, children were found to have 3% decreased protective effect of alpha+- thalassaemia polymorphisms (homozygotes and heterozygotes) against severe malaria although this was not statistically significant [ OR = 0.81 (95% CI = 0.5-1.5; P = 0.5) to OR = 0.78 (95% CI = 0.4-1.5; P = 0.44)]. We conclude that Glutathione-S-transferase-pi1 polymorphism increases risk of developing severe malaria due to Plasmodium falciparum in children. The observed inverse relationship between GSTP1 polymorphisms and alpha+-thalassaemia to children with severe malaria need further investigation.