Malaria infection induces oxidative stress in the host cells. Antioxidant enzymes such as glutathione S-transferases (GSTs) are responsible for fighting reactive oxygen species and reduction of oxidative stress. Common GST polymorphisms have been associated with susceptibility to different diseases whose pathologies involve oxidative stress. In this study, we tested the hypothesis that GST polymorphisms that lead to reduced or lack of enzyme activity are associated with severe Plasmodium falciparum malarial anemia. We studied the genotypic distribution of GSTM1, GSTT1, and GSTP1 polymorphisms between mild malaria (N = 107) and severe malarial anemia (N = 50) in Tanzanian children. We did not find a significant relationship with the GSTT1 polymorphism. GSTM1-null was higher in the severe malaria anemia group but the difference was not significant (P = 0.08). However, a significant association of GSTP1 I105V genotype with severe malarial anemia was discovered (26.0% against 10.3% mild malaria, P = 0.004). We concluded that GSTP1 and possibly GSTM1 may protect against severe falciparum malaria in children.