Serum samples from Ugandan residents of a malaria-hyperendemic region were tested by enzyme-linked immunosorbent assay for reactivity against recombinant constructs of the 47 (SE47')- and 50 (SE50A)-kDa fragments of Plasmodium falciparum serine repeat antigen (SERA). Immunoglobulin (Ig) G3 and IgG1 were the predominant subclass responses to SE47' and SE50A, respectively. The geometric mean optical density (OD) for IgG3 anti-SE47' was significantly lower in children < 15 years compared with adults > or = 15 years (P < 0.0001). By contrast, the geometric mean IgG1 anti-SE50A was slightly higher in children compared with adults (P < 0.01). The proportion of high responders (ODs > 0.5) to SE47' was significantly lower in children compared with adults (P < 0.001), whereas the proportion of high responders to SE50A was comparable in children and adults (P = 0.07). This first detailed study of SERA in a malaria-hyperendemic region suggests that natural human IgG3 anti-SE47' might be associated with immunity to malaria.