The sickle cell trait (HbAS) protects against severe Plasmodium falciparum malaria in young African children. We investigated the extent of the association between HbAS and antibodies directed to parasite-derived variant surface antigens (VSAs) on the membrane of infected erythrocytes. We measured immunoglobulin G (IgG) responses with specificity for VSAs of 2 heterologous parasite isolates in 458 Gabonese children aged between 6 months and 11 years. Logistic regression analyses showed a highly significant independent association (P<.001) between carriage of HbAS and the presence of IgG anti-VSA responses; this association was related specifically to IgG1 and IgG4 subclasses in the anti-VSA profile. IgG2 and IgG3 anti-VSA responses were both independently associated with older age, consistent with the pattern observed in semi-immune adults. The results imply that enhanced levels of cross-reactive anti-VSA responses in children with HbAS may be intimately associated with the protection they have against malaria.