Alpha⁺-thalassaemia is well known for conferring partial protection to 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 3 and 15 years with mild and severe malaria were retrieved and determined by polymerase chain reaction. Children with Glutathione-S-transferase-pi 1 ( GSTP 1)-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 in Korogwe District, north- eastern, Tanzania. In the presence of Glutathione-S-transferase-pi 1 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-pi 1 polymorphism increases risk of developing severe malaria due to Plasmodium falciparum in children. The observed inverse relationship between GSTP 1 polymorphisms and alpha⁺-thalassaemia to children with severe malaria need further investigation.