Abstract Background: The complexity and diversity of the antibody immune response to the antigen repertoire of a pathogen has long been appreciated. Although it has been recognized that the detection of antibodies against multiple antigens dramatically improves the clinical sensitivity and specificity of diagnostic assays, the prognostic value of serum reactivity profiles against multiple microbial antigens in protection has not been investigated. Methods: Using malaria as a model we investigated whether antigen reactivity profiles in serum of children with different levels of clinical immunity to Plasmodium falciparum malaria correlated with protection. We developed a microarray immunoassay of 18 recombinant antigens derived from 4 leading blood-stage vaccine candidates for P. falciparum [merozoite surface protein 1 (MSP1), MSP2, MSP3, and apical membrane antigen (AMA)-1]. Associations between observed reactivity profiles and clinical status were sought using k-means clustering and phylogenetic networks. Results: The antibody immune response was unexpectedly complex, with different combinations of antigens recognized in different children. Serum reactivity to individual antigens did not correlate with immune status. By contrast, combined recognition of AMA-1 and allelic variants of MSP2 was significantly associated with protection against clinical malaria. This finding was confirmed independently by k-means clustering and phylogenetic networking. Conclusions: The analysis of reactivity profiles provides a wealth of novel information about the immune response against microbial organisms that would pass unnoticed in analysis of reactivity to antigens individually. Extension of this approach to a large fraction of the proteome may expedite the identification of correlates of protection and vaccine development against microbial diseases.